Journal articles: 'Α-Synuclein (SNCA)'

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Zhang, Xue-Ming, Sabina Anwar, Yongsoo Kim, Jennifer Brown, Isabelle Comte, Huan Cai, Ning-Ning Cai, Richard Wade-Martins, and Francis G. Szele. "The A30P α-synuclein mutation decreases subventricular zone proliferation." Human Molecular Genetics 28, no. 14 (March 19, 2019): 2283–94. http://dx.doi.org/10.1093/hmg/ddz057.

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Abstract Parkinson's disease (PD) is associated with olfactory defects in addition to dopaminergic degeneration. Dopaminergic signalling is necessary for subventricular zone (SVZ) proliferation and olfactory bulb (OB) neurogenesis. Alpha-synuclein (α-syn or Snca) modulates dopaminergic neurotransmission, and SNCA mutations cause familial PD, but how α-syn and its mutations affect adult neurogenesis is unclear. To address this, we studied a bacterial artificial chromosome transgenic mouse expressing the A30P SNCA familial PD point mutation on an Snca−/− background. We confirmed that the SNCA-A30P transgene recapitulates endogenous α-syn expression patterns and levels by immunohistochemical detection of endogenous α-syn in a wild-type mouse and transgenic SNCA-A30P α-syn protein in the forebrain. The number of SVZ stem cells (BrdU+GFAP+) was decreased in SNCA-A30P mice, whereas proliferating (phospho-histone 3+) cells were decreased in Snca−/− and even more so in SNCA-A30P mice. Similarly, SNCA-A30P mice had fewer Mash1+ transit-amplifying SVZ progenitor cells but Snca−/− mice did not. These data suggest the A30P mutation aggravates the effect of Snca loss in the SVZ. Interestingly, calbindin+ and calretinin (CalR)+ periglomerular neurons were decreased in both Snca−/−, and SNCA-A30P mice but tyrosine hydroxylase+ periglomerular OB neurons were only decreased in Snca−/− mice. Cell death decreased in the OB granule layer of Snca−/− and SNCA-A30P mice. In the same region, CalR+ numbers increased in Snca−/− and SNCA-A30P mice. Thus, α-syn loss and human A30P SNCA decrease SVZ proliferation, cell death in the OB and differentially alter interneuron numbers. Similar disruptions in human neurogenesis may contribute to the olfactory deficits, which are observed in PD.

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Di Leva, Francesca Di, Michele Filosi, Lisa Oyston, Erica Silvestri, Anne Picard, Alexandros A. Lavdas, Evy Lobbestael, et al. "Increased Levels of the Parkinson’s Disease-Associated Gene ITPKB Correlate with Higher Expression Levels of α-Synuclein, Independent of Mutation Status." International Journal of Molecular Sciences 24, no. 3 (January 19, 2023): 1984. http://dx.doi.org/10.3390/ijms24031984.

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Autosomal dominant mutations in the gene encoding α-synuclein (SNCA) were the first to be linked with hereditary Parkinson’s disease (PD). Duplication and triplication of SNCA has been observed in PD patients, together with mutations at the N-terminal of the protein, among which A30P and A53T influence the formation of fibrils. By overexpressing human α-synuclein in the neuronal system of Drosophila, we functionally validated the ability of IP3K2, an ortholog of the GWAS identified risk gene, Inositol-trisphosphate 3-kinase B (ITPKB), to modulate α-synuclein toxicity in vivo. ITPKB mRNA and protein levels were also increased in SK-N-SH cells overexpressing wild-type α-synuclein, A53T or A30P mutants. Kinase overexpression was detected in the cytoplasmatic and in the nuclear compartments in all α-synuclein cell types. By quantifying mRNAs in the cortex of PD patients, we observed higher levels of ITPKB mRNA when SNCA was expressed more (p < 0.05), compared to controls. A positive correlation was also observed between SNCA and ITPKB expression in the cortex of patients, which was not seen in the controls. We replicated this observation in a public dataset. Our data, generated in SK-N-SH cells and in cortex from PD patients, show that the expression of α-synuclein and ITPKB is correlated in pathological situations.

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Zhang, Peiyuan, Hye-Jin Park, Jie Zhang, Eunsung Junn, Ryan J. Andrews, Sai Pradeep Velagapudi, Daniel Abegg, et al. "Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA." Proceedings of the National Academy of Sciences 117, no. 3 (January 3, 2020): 1457–67. http://dx.doi.org/10.1073/pnas.1905057117.

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Many proteins are refractory to targeting because they lack small-molecule binding pockets. An alternative to drugging these proteins directly is to target the messenger (m)RNA that encodes them, thereby reducing protein levels. We describe such an approach for the difficult-to-target protein α-synuclein encoded by the SNCA gene. Multiplication of the SNCA gene locus causes dominantly inherited Parkinson’s disease (PD), and α-synuclein protein aggregates in Lewy bodies and Lewy neurites in sporadic PD. Thus, reducing the expression of α-synuclein protein is expected to have therapeutic value. Fortuitously, the SNCA mRNA has a structured iron-responsive element (IRE) in its 5′ untranslated region (5′ UTR) that controls its translation. Using sequence-based design, we discovered small molecules that target the IRE structure and inhibit SNCA translation in cells, the most potent of which is named Synucleozid. Both in vitro and cellular profiling studies showed Synucleozid directly targets the α-synuclein mRNA 5′ UTR at the designed site. Mechanistic studies revealed that Synucleozid reduces α-synuclein protein levels by decreasing the amount of SNCA mRNA loaded into polysomes, mechanistically providing a cytoprotective effect in cells. Proteome- and transcriptome-wide studies showed that the compound’s selectivity makes Synucleozid suitable for further development. Importantly, transcriptome-wide analysis of mRNAs that encode intrinsically disordered proteins revealed that each has structured regions that could be targeted with small molecules. These findings demonstrate the potential for targeting undruggable proteins at the level of their coding mRNAs. This approach, as applied to SNCA, is a promising disease-modifying therapeutic strategy for PD and other α-synucleinopathies.

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Martínez-Rodríguez, Tania Yadira, and Mauricio Rey-Buitrago. "Physiological, molecular and genetic aspects of alpha-synuclein and its correlation with high alcohol consumption." Revista de la Facultad de Medicina 67, no. 3 (July 1, 2019): 315–22. http://dx.doi.org/10.15446/revfacmed.v67n3.69962.

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Introduction: Significant changes in the expression of α-synuclein (SNCA) can be seen in subjects with high alcohol consumption, altering neuroprotection and causing changes in the reward system.Objective: To present state-of-the-art studies on the physiological, molecular and genetic aspects of SNCA related to high alcohol consumption.Materials and methods: A search of records published from 2007 to 2017 was carried out in PUBMED, ScienceDirect and Cochrane with the terms alpha-synuclein, alcoholism, genetic polymorphism, gene expression, DNA methylation and molecular biology.Results: The search yielded 1 331 references, of which 51 full-texts were selected. The results describe the current evidence of the physiological and pathological aspects of α-synuclein (SNCA) and the genetic and epigenetic changes related to its expression in people with high alcohol consumption.Conclusions: The evidence suggests that a differential expression of α-synuclein (SNCA) is found in subjects with high alcohol consumption, as a result of modifications in the genetic and epigenetic mechanisms, leading to physipathological neuroadaptations. SNCA is a promising marker in the field of alcoholism research; therefore, more studies are required in this regard, taking into account the genetic heterogeneity of each population.

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Aloy, Nirjhar M., Michael W. Graner, Christina Coughlan, Sergey V. Slepenkov, Sahar Shekoohi, and Stephan N. Witt. "Abstract 1575: Knocking out alpha synuclein causes decreased release of extracellular vesicles in melanoma cells." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1575. http://dx.doi.org/10.1158/1538-7445.am2022-1575.

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Abstract The purpose of this study is to understand the role of α-synuclein in the regulation of the trafficking and release of modulators of metastasis in melanoma. Metastasis causes melanoma-induced death and 5-year survival rates, subsequent to metastasis to regional lymph nodes or distal organs, of 9% and 4%, respectively, hence novel therapeutic targets are required to control metastasis. Emerging evidence suggests that α-synuclein, a 14.4 KDa protein, which is a key player in Parkinson’s disease, is significantly correlated with melanoma progression. Our hypothesis is that α-synuclein positively regulates the release of extracellular vesicles. Extracellular vesicles (EVs) have been shown to be important in tumor metastasis, immune modulation and chemoresistance. The rationale for this hypothesis is that α-synuclein is a unique membrane-associated catalyst of endocytosis and exocytosis, and, specifically, synuclein regulates neurotransmitter release through SNARE complex assembly and the dilation of the fusion pore. The objective of the study is to measure the concentration of extracellular vesicles in the conditioned media from wild type SK-MEL-28 melanoma cells, SNCA knock out cells, and rescued SNCA-KO cells (where α-synuclein is re-expressed in KO cells via lentivirus) using Nanoparticle Tracking Analysis. The expected result was that knocking out SNCA would decrease the number of EVs released per cell relative to wild type control cells. To this end, we grew wild type, SNCA-KO and rescued SNCA-KO cells for 48 hours at 37°C and collected conditioned media. EVs were extracted from each conditioned medium using the ExoQuick-TC kit (Systems Bioscience) and stored at -80°C. EVs were characterized by PAGE followed by western blotting for common EV-markers and EV samples were shipped to the University of Colorado for Nanoparticle Tracking. Here we report a significant reduction in the concentration of EVs in SNCA-KO cell lines compared to control cells (P=0.0123), an effect that was rescued upon re-expression of α-synuclein in knock-out cells (P<0.01). Unpublished data from our lab suggests that invasion and migration are significantly reduced in SNCA-KO melanoma compared to control cells, a pathological outcome that returns in rescued SNCA-KO cells. These observations point to considering α-synuclein as a therapeutic target for regulating the release of pro-metastatic factors in extracellular vesicles, an intervention that would have important health implications as a novel therapeutic approach in melanoma. Work is ongoing in our lab to elucidate the mechanistic details of how α-synuclein promotes EV release. Citation Format: Nirjhar M. Aloy, Michael W. Graner, Christina Coughlan, Sergey V. Slepenkov, Sahar Shekoohi, Stephan N. Witt. Knocking out alpha synuclein causes decreased release of extracellular vesicles in melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1575.

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Kawahata, Ichiro, David I. Finkelstein, and Kohji Fukunaga. "Pathogenic Impact of α-Synuclein Phosphorylation and Its Kinases in α-Synucleinopathies." International Journal of Molecular Sciences 23, no. 11 (June 1, 2022): 6216. http://dx.doi.org/10.3390/ijms23116216.

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α-Synuclein is a protein with a molecular weight of 14.5 kDa and consists of 140 amino acids encoded by the SNCA gene. Missense mutations and gene duplications in the SNCA gene cause hereditary Parkinson’s disease. Highly phosphorylated and abnormally aggregated α-synuclein is a major component of Lewy bodies found in neuronal cells of patients with sporadic Parkinson’s disease, dementia with Lewy bodies, and glial cytoplasmic inclusion bodies in oligodendrocytes with multiple system atrophy. Aggregated α-synuclein is cytotoxic and plays a central role in the pathogenesis of the above-mentioned synucleinopathies. In a healthy brain, most α-synuclein is unphosphorylated; however, more than 90% of abnormally aggregated α-synuclein in Lewy bodies of patients with Parkinson’s disease is phosphorylated at Ser129, which is presumed to be of pathological significance. Several kinases catalyze Ser129 phosphorylation, but the role of phosphorylation enzymes in disease pathogenesis and their relationship to cellular toxicity from phosphorylation are not fully understood in α-synucleinopathy. Consequently, this review focuses on the pathogenic impact of α-synuclein phosphorylation and its kinases during the neurodegeneration process in α-synucleinopathy.

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Reiszadeh Jahromi, Samaneh, S. R. Ramesh, David I. Finkelstein, and Mohammad Haddadi. "α-Synuclein E46K Mutation and Involvement of Oxidative Stress in a Drosophila Model of Parkinson’s Disease." Parkinson's Disease 2021 (July 3, 2021): 1–12. http://dx.doi.org/10.1155/2021/6621507.

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Parkinson’s disease (PD) is an age-associated neurodegenerative condition in which some genetic variants are known to increase disease susceptibility on interaction with environmental factors inducing oxidative stress. Different mutations in the SNCA gene are reported as the major genetic contributors to PD. E46K mutation pathogenicity has not been investigated as intensive as other SNCA gene mutations including A30P and A53T. In this study, based on the GAL4-UAS binary genetic tool, transgenic Drosophila melanogaster flies expressing wild-type and E46K-mutated copies of the human SNCA gene were constructed. Western blotting, immunohistochemical analysis, and light and confocal microscopy of flies’ brains were undertaken along with the survival rate measurement, locomotor function assay, and ethanol and paraquat (PQ) tolerance to study α-synuclein neurotoxicity. Biochemical bioassays were carried out to investigate the activity of antioxidant enzymes and alterations in levels of oxidative markers following damages induced by human α-synuclein to the neurons of the transgenic flies. Overexpression of human α-synuclein in the central nervous system of these transgenic flies led to disorganized ommatidia structures and loss of dopaminergic neurons. E46K α-synuclein caused remarkable climbing defects, reduced survivorship, higher ethanol sensitivity, and increased PQ-mediated mortality. A noticeable decline in activity of catalase and superoxide dismutase enzymes besides considerable increase in the levels of lipid peroxidation and reactive oxygen species was observed in head capsule homogenates of α-synuclein-expressing flies, which indicates obvious involvement of oxidative stress as a causal factor in SNCAE46K neurotoxicity. In all the investigations, E46K copy of the SNCA gene was found to impose more severe defects when compared to wild-type SNCA. It can be concluded that the constructed Drosophila models developed PD-like symptoms that facilitate comparative studies of molecular and cellular pathways implicated in the pathogenicity of different α-synuclein mutations.

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Zhang, Jing-Xing, Wei-Fang Tong, Ming Jiang, Kai-Ge Zhou, Xue-rui Xiang, Yi-jing He, Zhuo-yu Zhang, Qiang Guan, and Ling-Jing Jin. "MANF Inhibits α-Synuclein Accumulation through Activation of Autophagic Pathways." Oxidative Medicine and Cellular Longevity 2022 (July 8, 2022): 1–19. http://dx.doi.org/10.1155/2022/7925686.

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Progressive accumulation of misfolded SNCA/α-synuclein is key to the pathology of Parkinson’s disease (PD). Drugs aiming at degrading SNCA may be an efficient therapeutic strategy for PD. Our previous study showed that mesencephalic astrocyte-derived neurotrophic factor (MANF) facilitated the removal of misfolded SNCA and rescued dopaminergic (DA) neurons, but the underlying mechanisms remain unknown. In this study, we showed that AAV8-MANF relieved Parkinsonian behavior in rotenone-induced PD model and reduced SNCA accumulation in the substantia nigra. By establishing wildtype (WT) SNCA overexpression cellular model, we found that chaperone-mediated-autophagy (CMA) and macroautophagy were both participated in MANF-mediated degradation of SNCAWT. Nuclear factor erythroid 2-related factor (Nrf2) was activated to stimulating macroautophagy activity when CMA pathway was impaired. Using A53T mutant SNCA overexpression cellular model to mimic CMA dysfunction situation, we concluded that macroautophagy rather than CMA was responsible to the degradation of SNCAA53T, and this degradation was mediated by Nrf2 activation. Hence, our findings suggested that MANF has potential therapeutic value for PD. Nrf2 and its role in MANF-mediated degradation may provide new sights that target degradation pathways to counteract SNCA pathology in PD.

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Taguchi, Tomoyuki, Masashi Ikuno, Mari Hondo, Laxmi Kumar Parajuli, Katsutoshi Taguchi, Jun Ueda, Masanori Sawamura, et al. "α-Synuclein BAC transgenic mice exhibit RBD-like behaviour and hyposmia: a prodromal Parkinson’s disease model." Brain 143, no. 1 (December 9, 2019): 249–65. http://dx.doi.org/10.1093/brain/awz380.

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Abstract Parkinson’s disease is one of the most common movement disorders and is characterized by dopaminergic cell loss and the accumulation of pathological α-synuclein, but its precise pathogenetic mechanisms remain elusive. To develop disease-modifying therapies for Parkinson’s disease, an animal model that recapitulates the pathology and symptoms of the disease, especially in the prodromal stage, is indispensable. As subjects with α-synuclein gene (SNCA) multiplication as well as point mutations develop familial Parkinson’s disease and a genome-wide association study in Parkinson’s disease has identified SNCA as a risk gene for Parkinson’s disease, the increased expression of α-synuclein is closely associated with the aetiology of Parkinson’s disease. In this study we generated bacterial artificial chromosome transgenic mice harbouring SNCA and its gene expression regulatory regions in order to maintain the native expression pattern of α-synuclein. Furthermore, to enhance the pathological properties of α-synuclein, we inserted into SNCA an A53T mutation, two single-nucleotide polymorphisms identified in a genome-wide association study in Parkinson’s disease and a Rep1 polymorphism, all of which are causal of familial Parkinson’s disease or increase the risk of sporadic Parkinson’s disease. These A53T SNCA bacterial artificial chromosome transgenic mice showed an expression pattern of human α-synuclein very similar to that of endogenous mouse α-synuclein. They expressed truncated, oligomeric and proteinase K-resistant phosphorylated forms of α-synuclein in the regions that are specifically affected in Parkinson’s disease and/or dementia with Lewy bodies, including the olfactory bulb, cerebral cortex, striatum and substantia nigra. Surprisingly, these mice exhibited rapid eye movement (REM) sleep without atonia, which is a key feature of REM sleep behaviour disorder, at as early as 5 months of age. Consistent with this observation, the REM sleep-regulating neuronal populations in the lower brainstem, including the sublaterodorsal tegmental nucleus, nuclei in the ventromedial medullary reticular formation and the pedunculopontine nuclei, expressed phosphorylated α-synuclein. In addition, they also showed hyposmia at 9 months of age, which is consistent with the significant accumulation of phosphorylated α-synuclein in the olfactory bulb. The dopaminergic neurons in the substantia nigra pars compacta degenerated, and their number was decreased in an age-dependent manner by up to 17.1% at 18 months of age compared to wild-type, although the mice did not show any related locomotor dysfunction. In conclusion, we created a novel mouse model of prodromal Parkinson’s disease that showed RBD-like behaviour and hyposmia without motor symptoms.

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Patrakhanov, E. A., V. M. Pokrovsky, A. Yu Karagodina, A. M. Krayushkina, N. S. Zhunusov, A. V. Deykin, M. V. Korokin, M. V. Pokrovsky, and O. B. Altukhova. "DEVELOPMENT OF MURINE STEM CELLS WITH CONDITIONAL KNOCKOUT OF HUMANIZED SNCA GENE." Pharmacy & Pharmacology 10, no. 6 (February 12, 2023): 525–35. http://dx.doi.org/10.19163/2307-9266-2022-10-6-525-535.

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α-synuclein is one of the key molecular links in the pathogenesis of Parkinson’s disease. The accumulated data indicate that pathogenic mutations in the Snca gene are associated with the development of neurodegenerative brain damage, indicating the relevance of studying the synuclein neurobiological role.The aim of the study was to create a genetically modified clone of mouse stem cells with a conditional knockout of humanized α-synuclein, which can be used for the reinjection into mouse blastocysts, as well as for basic and applied in vitro research in the field of pathophysiology and neuropharmacology.Materials and methods. To create mouse stem cells with a conditional knockout of the humanized Snca gene, a previously obtained clone with the first Snca exon flanked by LoxP sites, was used. The CRISPR/Cas9-mediated homologous recombination system with donor DNA oligonucleotides of the human sites of the corresponding gene sites was used to humanize the fourth and fifth exons. Cas9 nuclease, single guide RNA, and donor DNA were transfected into mouse cells.Results. An approach to obtaining clones of mouse genetically modified stem cells expressing pathological humanized α-synuclein, has been proposed and implemented. The resulting clones were plated on Petri dishes for propagation and a further genetic analysis. Clone 126-2F4 was found out carrying the necessary genetic modifications. The results obtained are fundamentally important not only for understanding the development of the pathological process in α-synucleinopathies, but which is more important, for the development of new therapeutic approaches that will stop the extension of the human α-synuclein aggregation pathology throughout the nervous system, and the validation of these approaches in preclinical trials.Conclusion. As a result of the study, a strategy for CRISPR/Cas9-assisted homologous recombination in the genome of mouse embryonic stem cells has been developed to create a fully humanized Snca gene encoding α-synuclein, and the clone genome of mouse embryonic stem cells has been edited using a CRISPR technology. The RNA and DNA oligonucleotides necessary for the creation of RNP complexes that carry out a directed homologous recombination in the Snca locus of the mouse genome have been synthesized. The developed cell clone can serve to create a line of genetically modified mice that serve as a test system for pathophysiological and neuropharmacological studies associated with synucleinopathies. Herewith, before the induction of the Cre-dependent recombination, this line is a representative model for studying a biological role of mutant Snca. At the same time, after a Cre-dependent knockout activation, it is possible to imitate the pharmacological inhibition of α-synuclein, which is of particular interest for applied research in neuropharmacology.

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Koukouraki, Pelagia, and Epaminondas Doxakis. "Constitutive translation of human α-synuclein is mediated by the 5′-untranslated region." Open Biology 6, no. 4 (April 2016): 160022. http://dx.doi.org/10.1098/rsob.160022.

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Genetic and biochemical studies have established a central role for α-synuclein (SNCA) accumulation in the pathogenesis of Parkinson's disease. Uncovering and subsequently interfering with physiological mechanisms that control SNCA expression is one approach to limit disease progression. To this end, the long and GC-rich 5′-untranslated region (UTR) of SNCA, which is predicted to fold into stable hairpin and G-quadruplex RNA motifs, was investigated for its role in mRNA translation. Inclusion of SNCA 5′-UTR significantly induced expression of both SNCA and luciferase ORF constructs. This effect was not associated with a change in mRNA levels or differential nucleocytoplasmic shuttling. Further, the presence of the 5′-UTR enhanced SNCA synthesis when cap-dependent translation was attenuated with rapamycin treatment. Analysis using multiple methodologies revealed that the 5′-UTR harbours an internal ribosome entry site (IRES) element that spans most of its nucleotide sequence. Signals such as plasma-membrane depolarization, serum starvation and oxidative stress stimulated SNCA protein translation via its 5′-UTR as well as enhanced its IRES activity. Taken together, these data support the idea that the 5′-UTR is an important positive regulator of SNCA synthesis under diverse physiological and pathological conditions, explaining in part the abundance of SNCA in healthy neurons and its accumulation in degenerative cells.

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Ikeda, Aya, Kenya Nishioka, Hongrui Meng, Masashi Takanashi, Iwao Hasegawa, Tsuyoshi Inoshita, Kahori Shiba-Fukushima, et al. "Mutations in CHCHD2 cause α-synuclein aggregation." Human Molecular Genetics 28, no. 23 (October 10, 2019): 3895–911. http://dx.doi.org/10.1093/hmg/ddz241.

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Abstract Mutations in CHCHD2 are linked to a familial, autosomal dominant form of Parkinson’s disease (PD). The gene product may regulate mitochondrial respiratory function. However, whether mitochondrial dysfunction induced by CHCHD2 mutations further yields α-synuclein pathology is unclear. Here, we provide compelling genetic evidence that mitochondrial dysfunction induced by PD-linked CHCHD2 T61I mutation promotes α-synuclein aggregation using brain autopsy, induced pluripotent stem cells (iPSCs) and Drosophila genetics. An autopsy of an individual with CHCHD2 T61I revealed widespread Lewy pathology with both amyloid plaques and neurofibrillary tangles that appeared in the brain stem, limbic regions and neocortex. A prominent accumulation of sarkosyl-insoluble α-synuclein aggregates, the extent of which was comparable to that of a case with α-synuclein (SNCA) duplication, was observed in CHCHD2 T61I brain tissue. The prion-like activity and morphology of α-synuclein fibrils from the CHCHD2 T61I brain tissue were similar to those of fibrils from SNCA duplication and sporadic PD brain tissues. α-Synuclein insolubilization was reproduced in dopaminergic neuron cultures from CHCHD2 T61I iPSCs and Drosophila lacking the CHCHD2 ortholog or expressing the human CHCHD2 T61I. Moreover, the combination of ectopic α-synuclein expression and CHCHD2 null or T61I enhanced the toxicity in Drosophila dopaminergic neurons, altering the proteolysis pathways. Furthermore, CHCHD2 T61I lost its mitochondrial localization by α-synuclein in Drosophila. The mislocalization of CHCHD2 T61I was also observed in the patient brain. Our study suggests that CHCHD2 is a significant mitochondrial factor that determines α-synuclein stability in the etiology of PD.

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Sterling, Lori, Michael Walter, Dennis Ting, and Birgitt Schüle. "Discovery of functional non-coding conserved regions in the α-synuclein gene locus." F1000Research 3 (December 8, 2014): 259. http://dx.doi.org/10.12688/f1000research.3281.2.

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Several single nucleotide polymorphisms (SNPs) and the Rep-1 microsatellite marker of the α-synuclein ( SNCA) gene have consistently been shown to be associated with Parkinson’s disease, but the functional relevance is unclear. Based on these findings we hypothesized that conserved cis-regulatory elements in the SNCA genomic region regulate expression of SNCA, and that SNPs in these regions could be functionally modulating the expression of SNCA, thus contributing to neuronal demise and predisposing to Parkinson’s disease.In a pair-wise comparison of a 206kb genomic region encompassing the SNCA gene, we revealed 34 evolutionary conserved DNA sequences between human and mouse. All elements were cloned into reporter vectors and assessed for expression modulation in dual luciferase reporter assays. We found that 12 out of 34 elements exhibited either an enhancement or reduction of the expression of the reporter gene. Three elements upstream of the SNCA gene displayed an approximately 1.5 fold (p<0.009) increase in expression. Of the intronic regions, three showed a 1.5 fold increase and two others indicated a 2 and 2.5 fold increase in expression (p<0.002). Three elements downstream of the SNCA gene showed 1.5 fold and 2.5 fold increase (p<0.0009). One element downstream of SNCA had a reduced expression of the reporter gene of 0.35 fold (p<0.0009) of normal activity.Our results demonstrate that the SNCA gene contains cis-regulatory regions that might regulate the transcription and expression of SNCA. Further studies in disease-relevant tissue types will be important to understand the functional impact of regulatory regions and specific Parkinson’s disease-associated SNPs and its function in the disease process.

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Spillantini, Maria Grazia, Aspasia Divane, and Michel Goedert. "Assignment of Human α-Synuclein (SNCA) and β-Synuclein (SNCB) Genes to Chromosomes 4q21 and 5q35." Genomics 27, no. 2 (May 1995): 379–81. http://dx.doi.org/10.1006/geno.1995.1063.

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Ellis, Christopher E., Eric J. Murphy, Drake C. Mitchell, Mikhail Y. Golovko, Fernando Scaglia, Gwendolyn C. Barceló-Coblijn, and Robert L. Nussbaum. "Mitochondrial Lipid Abnormality and Electron Transport Chain Impairment in Mice Lacking α-Synuclein." Molecular and Cellular Biology 25, no. 22 (November 15, 2005): 10190–201. http://dx.doi.org/10.1128/mcb.25.22.10190-10201.2005.

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ABSTRACT The presynaptic protein α-synuclein, implicated in Parkinson disease (PD), binds phospholipids and has a role in brain fatty acid (FA) metabolism. In mice lacking α-synuclein (Snca −/−), total brain steady-state mass of the mitochondria-specific phospholipid, cardiolipin, is reduced 22% and its acyl side chains show a 51% increase in saturated FAs and a 25% reduction in essential n-6, but not n-3, polyunsaturated FAs. Additionally, 23% reduction in phosphatidylglycerol content, the immediate biosynthetic precursor of cardiolipin, was observed without alterations in the content of other brain phospholipids. Consistent with these changes, more ordered lipid head group and acyl chain packing with enhanced rotational motion of diphenylhexatriene (DPH) about its long axis were demonstrated in time-resolved DPH fluorescence lifetime experiments. These abnormalities in mitochondrial membrane properties were associated with a 15% reduction in linked complex I/III activity of the electron transport chain, without reductions in mitochondrial number, complex II/III activity, or individual complex I, II, III, or IV activity. Reduced complex I activity is thought to be a critical factor in the development of PD. Thus, altered membrane composition and structure and impaired complex I/III function in Snca −/− brain suggest a relationship between α-synuclein's role in brain lipid metabolism, mitochondrial function, and PD.

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Magistrelli, Luca, Elena Contaldi, and Cristoforo Comi. "The Impact of SNCA Variations and Its Product Alpha-Synuclein on Non-Motor Features of Parkinson’s Disease." Life 11, no. 8 (August 9, 2021): 804. http://dx.doi.org/10.3390/life11080804.

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Parkinson’s disease (PD) is a common and progressive neurodegenerative disease, caused by the loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain, which is clinically characterized by a constellation of motor and non-motor manifestations. The latter include hyposmia, constipation, depression, pain and, in later stages, cognitive decline and dysautonomia. The main pathological features of PD are neuronal loss and consequent accumulation of Lewy bodies (LB) in the surviving neurons. Alpha-synuclein (α-syn) is the main component of LB, and α-syn aggregation and accumulation perpetuate neuronal degeneration. Mutations in the α-syn gene (SNCA) were the first genetic cause of PD to be identified. Generally, patients carrying SNCA mutations present early-onset parkinsonism with severe and early non-motor symptoms, including cognitive decline. Several SNCA polymorphisms were also identified, and some of them showed association with non-motor manifestations. The functional role of these polymorphisms is only partially understood. In this review we explore the contribution of SNCA and its product, α-syn, in predisposing to the non-motor manifestations of PD.

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Hebron, Michaeline L., Irina Lonskaya, and Charbel E. H. Moussa. "Tyrosine kinase inhibition facilitates autophagic SNCA/α-synuclein clearance." Autophagy 9, no. 8 (August 14, 2013): 1249–50. http://dx.doi.org/10.4161/auto.25368.

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Brockhaus, Katrin, Michael R. R. Böhm, Harutyun Melkonyan, and Solon Thanos. "Age-related Beta-synuclein Alters the p53/Mdm2 Pathway and Induces the Apoptosis of Brain Microvascular Endothelial Cells In Vitro." Cell Transplantation 27, no. 5 (May 2018): 796–813. http://dx.doi.org/10.1177/0963689718755706.

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Increased β-synuclein (Sncb) expression has been described in the aging visual system. Sncb functions as the physiological antagonist of α-synuclein (Snca), which is involved in the development of neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases. However, the exact function of Sncb remains unknown. The aim of this study was to elucidate the age-dependent role of Sncb in brain microvascular endothelial cells (BMECs). BMECs were isolated from the cortices of 5- to 9-d-old Sprague-Dawley rats and were cultured with different concentrations of recombinant Sncb (rSncb) up to 72 h resembling to some degree age-related as well as pathophysiological conditions. Viability, apoptosis, expression levels of Snca, and the members of phospholipase D2 (Pld2)/ p53/ Mouse double minute 2 homolog (Mdm2)/p19(Arf) pathway, response in RAC-alpha serine/threonine-protein kinase (Akt), and stress-mediating factors such as heme oxygenase (decycling) 1 (Hmox) and Nicotinamide adenine dinucleotide phosphate oxygenase 4 (Nox4) were examined. rSncb-induced effects were confirmed through Sncb small interfering RNA (siRNA) knockdown in BMECs. We demonstrated that the viability decreases, while the rate of apoptosis underly dose-dependent alterations. For example, apoptosis increases in BMECs following the treatment with higher dosed rSncb. Furthermore, we observed a decrease in Snca immunostaining and messenger RNA (mRNA) levels following the exposure to higher rScnb concentrations. Akt was shown to be downregulated and pAkt upregulated by this treatment, which was accompanied by a dose-independent increase in p19(Arf) levels and enhanced intracellular Mdm2 translocation in contrast to a dose-dependent p53 activation. Moreover, Pld2 activity was shown to be induced in rSncb-treated BMECs. The expression of Hmox and Nox4 after Sncb treatment was altered on BEMCs. The obtained results demonstrate dose-dependent effects of Sncb on BMECs in vitro. For example, the p53-mediated and Akt-independent apoptosis together with the stress-mediated response of BMECs related to exposure of higher SNCB concentrations may reflect the increase in Sncb with duration of culture as well as its impact on cell decay. Further studies, expanding on the role of Sncb, may help understand its role in the neurodegenerative diseases.

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Guhathakurta, Subhrangshu, Min Kyung Song, Sambuddha Basu, Goun Je, Ana Clara Cristovao, and Yoon-Seong Kim. "Regulation of Αlpha-Synuclein Gene (SNCA) by Epigenetic Modifier TET1 in Parkinson Disease." International Neurourology Journal 26, Suppl 2 (November 30, 2022): S85–93. http://dx.doi.org/10.5213/inj.2222206.103.

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Purpose: Deregulation of SNCA encoding α-synuclein (α-SYN) has been associated with both the familial and sporadic forms of Parkinson disease (PD). Epigenetic regulation plays a crucial role in PD. The intron1 of SNCA harbors a large unmethylated CpG island. Ten-eleven translocation methylcytosine dioxygenase 1 (TET1), a CpG island binding protein, can repress gene expression by occupying hypomethylated CpG-rich promoters, and therefore SNCA could be a target for TET1. We investigated whether TET1 binds to SNCA-intron1 and regulates gene expression.Methods: The dopaminergic neuronal cell line, ReNcell VM, was used. Reverse transcription-polymerase chain reaction (RT-PCR), real time-quantitative PCR, Western blot, dot-blot, and Chromatin immunoprecipitation were conducted. The substantia nigra tissues of postmortem PD samples were used to confirm the level of TET1 expression.Results: In the human dopaminergic cell line, ReNcell VM, overexpression of the DNA-binding domain of TET1 (TET1-CXXC) led to significant repression of α-SYN. On the contrary, knocking down of TET1 led to significantly higher expression of α-SYN. However, overexpression of the DNA-hydroxymethylating catalytic domain of TET1 failed to change the expression of α-SYN. Altogether, we showed that TET1 is a repressor for SNCA, and a CXXC domain of TET1 is the primary mediator for this repressive action independent of its hydroxymethylation activity. TET1 levels in PD patients are significantly lower than that in the controls.Conclusions: We identified that TET1 acts as a repressor for SNCA by binding the intron1 regions of the gene. As a high level of α-SYN is strongly implicated in the pathogenesis of PD, discovering a repressor for the gene encoding α-SYN is highly important for developing novel therapeutic strategies for the disease.

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Okuda, Shinya, Takeo Nakayama, Norihito Uemura, Rie Hikawa, Masashi Ikuno, Hodaka Yamakado, Haruhisa Inoue, et al. "Striatal-Inoculation of α-Synuclein Preformed Fibrils Aggravated the Phenotypes of REM Sleep without Atonia in A53T BAC-SNCA Transgenic Mice." International Journal of Molecular Sciences 23, no. 21 (November 2, 2022): 13390. http://dx.doi.org/10.3390/ijms232113390.

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Accumulation of α-synuclein (α-syn) is the pathological hallmark of α-synucleinopathy. Rapid eye movement (REM) sleep behavior disorder (RBD) is a pivotal manifestation of α-synucleinopathy including Parkinson’s disease (PD). RBD is clinically confirmed by REM sleep without atonia (RWA) in polysomnography. To accurately characterize RWA preceding RBD and their underlying α-syn pathology, we inoculated α-syn preformed fibrils (PFFs) into the striatum of A53T human α-syn BAC transgenic (A53T BAC-SNCA Tg) mice which exhibit RBD-like phenotypes with RWA. RWA phenotypes were aggravated by PFFs-inoculation in A53T BAC-SNCA Tg mice at 1 month after inoculation, in which prominent α-syn pathology in the pedunculopontine nucleus (PPN) was observed. The intensity of RWA phenotype could be dependent on the severity of the underlying α-syn pathology.

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Chen, Vivian, Malik Moncalvo, Dominic Tringali, Lidia Tagliafierro, Ahila Shriskanda, Ekaterina Ilich, Wendy Dong, Boris Kantor, and Ornit Chiba-Falek. "The mechanistic role of alpha-synuclein in the nucleus: impaired nuclear function caused by familial Parkinson’s disease SNCA mutations." Human Molecular Genetics 29, no. 18 (September 15, 2020): 3107–21. http://dx.doi.org/10.1093/hmg/ddaa183.

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Abstract Alpha-synuclein SNCA has been implicated in the etiology of Parkinson’s disease (PD); however, the normal function of alpha-synuclein protein and the pathway that mediates its pathogenic effect is yet to be discovered. We investigated the mechanistic role of SNCA in the nucleus utilizing isogenic human-induced pluripotent stem cells-derived neurons from PD patients with autosomal dominant mutations, A53T and SNCA-triplication, and their corresponding corrected lines by genome- and epigenome-editing. Comparisons of shape and integrity of the nuclear envelope and its resistance to stresses found that both mutations result in similar nuclear envelope perturbations that were reversed in the isogenic mutation-corrected cells. Further mechanistic studies showed that SNCA mutation has adverse effects on the nucleus by trapping Ras-related nuclear protein (RAN) and preventing it from transporting key nuclear proteins such as, DNMT3A, for maintaining normal nuclear function. For the first time, we proposed that α-syn interacts with RAN and normally functions in the nucleocytoplasmic transport while exerts its pathogenic effect by sequestering RAN. We suggest that defects in the nucleocytoplasmic transport components may be a general pathomechanistic driver of neurodegenerative diseases.

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Wang, Yiru A., Lisa van Sluijs, Yu Nie, Mark G. Sterken, Simon C. Harvey, and Jan E. Kammenga. "Genetic Variation in Complex Traits in Transgenic α-Synuclein Strains of Caenorhabditis elegans." Genes 11, no. 7 (July 11, 2020): 778. http://dx.doi.org/10.3390/genes11070778.

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Different genetic backgrounds can modify the effect of mutated genes. Human α-synuclein (SNCA) gene encodes α-synuclein, and its oligomeric complexes accumulate with age and mediate the disruption of cellular homeostasis, resulting in the neuronal death that is characteristic of Parkinson’s Disease. Polymorphic variants modulate this complex pathologic mechanism. Previously, we constructed five transgenic introgression lines of a Caenorhabditis elegans model of α-synuclein using genetic backgrounds that are genetically diverse from the canonical wild-type Bristol N2. A gene expression analysis revealed that the α-synuclein transgene differentially affects genome-wide transcription due to background modifiers. To further investigate how complex traits are affected in these transgenic lines, we measured the α-synuclein transgene expression, the overall accumulation of the fusion protein of α-synuclein and yellow fluorescent protein (YFP), the lysosome-related organelles, and the body size. By using quantitative PCR (qPCR), we demonstrated stable and similar expression levels of the α-synuclein transgene in different genetic backgrounds. Strikingly, we observed that the levels of the a-synuclein:YFP fusion protein vary in different genetic backgrounds by using the COPAS™ biosorter. The quantification of the Nile Red staining assay demonstrates that α-synuclein also affects lysosome-related organelles and body size. Our results show that the same α-synuclein introgression in different C. elegans backgrounds can produces differing effects on complex traits due to background modifiers.

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Lee, Mei-Hwa, Jeng-Shiung Jan, James L. Thomas, Yuan-Pin Shih, Jin-An Li, Chien-Yu Lin, Tooru Ooya, et al. "Cellular Therapy Using Epitope-Imprinted Composite Nanoparticles to Remove α-Synuclein from an In Vitro Model." Cells 11, no. 16 (August 19, 2022): 2584. http://dx.doi.org/10.3390/cells11162584.

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Several degenerative disorders of the central nervous system, including Parkinson’s disease (PD), are related to the pathological aggregation of proteins. Antibodies against toxic disease proteins, such as α-synuclein (SNCA), are therefore being developed as possible therapeutics. In this work, one peptide (YVGSKTKEGVVHGVA) from SNCA was used as the epitope to construct magnetic molecularly imprinted composite nanoparticles (MMIPs). These composite nanoparticles were characterized by dynamic light scattering (DLS), high-performance liquid chromatography (HPLC), isothermal titration calorimetry (ITC), Brunauer–Emmett–Teller (BET) analysis, and superconducting quantum interference device (SQUID) analysis. Finally, the viability of brain endothelial cells that were treated with MMIPs was measured, and the extraction of SNCA from CRISPR/dCas9a-activated HEK293T cells from the in vitro model system was demonstrated for the therapeutic application of MMIPs.

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Hong, Chien-Tai, Kai-Yun Chen, Weu Wang, Jing-Yuan Chiu, Dean Wu, Tsu-Yi Chao, Chaur-Jong Hu, Kai-Yin Chau, and Oluwaseun Bamodu. "Insulin Resistance Promotes Parkinson’s Disease through Aberrant Expression of α-Synuclein, Mitochondrial Dysfunction, and Deregulation of the Polo-Like Kinase 2 Signaling." Cells 9, no. 3 (March 17, 2020): 740. http://dx.doi.org/10.3390/cells9030740.

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Background: Insulin resistance (IR), considered a hallmark of diabetes at the cellular level, is implicated in pre-diabetes, results in type 2 diabetes, and negatively affects mitochondrial function. Diabetes is increasingly associated with enhanced risk of developing Parkinson’s disease (PD); however, the underlying mechanism remains unclear. This study investigated the probable culpability of IR in the pathogenesis of PD. Methods: Using MitoPark mice in vivo models, diabetes was induced by a high-fat diet in the in vivo models, and IR was induced by protracted pulse-stimulation with 100 nM insulin treatment of neuronal cells, in vitro to determine the molecular mechanism(s) underlying altered cellular functions in PD, including mitochondrial dysfunction and α-synuclein (SNCA) aberrant expression. Findings: We observed increased SNCA expression in the dopaminergic (DA) neurons of both the wild-type and diabetic MitoPark mice, coupled with enhanced degeneration of DA neurons in the diabetic MitoPark mice. Ex vivo, in differentiated human DA neurons, IR was associated with increased SNCA and reactive oxygen species (ROS) levels, as well as mitochondrial depolarization. Moreover, we demonstrated concomitant hyperactivation of polo-like kinase-2 (PLK2), and upregulated p-SNCA (Ser129) and proteinase K-resistant SNCA proteins level in IR SH-SY5Y cells, however the inhibition of PLK2 reversed IR-related increases in phosphorylated and total SNCA. Similarly, the overexpression of peroxisome proliferator-activated receptor-γ coactivator 1-alpha (PGC)-1α suppressed ROS production, repressed PLK2 hyperactivity, and resulted in downregulation of total and Ser129-phosphorylated SNCA in the IR SH-SY5Y cells. Conclusions: These findings demonstrate that IR-associated diabetes promotes the development and progression of PD through PLK2-mediated mitochondrial dysfunction, upregulated ROS production, and enhanced SNCA signaling, suggesting the therapeutic targetability of PLK2 and/or SNCA as potential novel disease-modifying strategies in patients with PD.

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Tiwari, Shubhangini, Abhishek Singh, Parul Gupta, and Sarika Singh. "UBA52 Is Crucial in HSP90 Ubiquitylation and Neurodegenerative Signaling during Early Phase of Parkinson’s Disease." Cells 11, no. 23 (November 25, 2022): 3770. http://dx.doi.org/10.3390/cells11233770.

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Protein aggregation is one of the major pathological events in age-related Parkinson’s disease (PD) pathology, predominantly regulated by the ubiquitin–proteasome system (UPS). UPS essentially requires core component ubiquitin; however, its role in PD pathology is obscure. This study aimed to investigate the role of ubiquitin-encoding genes in sporadic PD pathology. Both cellular and rat models of PD as well as SNCA C57BL/6J-Tg (Th-SNCA*A30P*A53T)39 Eric/J transgenic mice showed a decreased abundance of UBA52 in conjunction with significant downregulation of tyrosine hydroxylase (TH) and neuronal death. In silico predictions, mass spectrometric analysis, and co-immunoprecipitation findings suggested the protein–protein interaction of UBA52 with α-synuclein, HSP90 and E3-ubiquitin ligase CHIP, and its co-localization with α-synuclein in the mitochondrion. Next, in vitro ubiquitylation assay indicated an imperative requirement of the lysine-63 residue of UBA52 in CHIP-mediated HSP90 ubiquitylation. Myc-UBA52 expressed neurons inhibited alteration in PD-specific markers such as α-synuclein and TH protein along with increased proteasome activity in diseased conditions. Furthermore, Myc-UBA52 expression inhibited the altered protein abundance of HSP90 and its various client proteins, HSP75 (homolog of HSP90 in mitochondrion) and ER stress-related markers during early PD. Taken together, the data highlights the critical role of UBA52 in HSP90 ubiquitylation in parallel to its potential contribution to the modulation of various disease-related neurodegenerative signaling targets during the early phase of PD pathology.

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Lopez, Ana, Alena Gorb, Nuno Palha, Angeleen Fleming, and David C. Rubinsztein. "A New Zebrafish Model to Measure Neuronal α-Synuclein Clearance In Vivo." Genes 13, no. 5 (May 12, 2022): 868. http://dx.doi.org/10.3390/genes13050868.

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The accumulation and aggregation of α-synuclein (α-SYN) is a common characteristic of synucleinopathies, such as Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB) or Multiple System Atrophy (MSA). Multiplications of the wildtype gene of α-SYN (SNCA) and most point mutations make α-SYN more aggregate-prone, and are associated with mitochondrial defects, trafficking obstruction, and impaired proteostasis, which contribute to elevated neuronal death. Here, we present new zebrafish models expressing either human wildtype (wt), or A53T mutant, α-SYN that recapitulate the above-mentioned hallmarks of synucleinopathies. The appropriate clearance of toxic α-SYN has been previously shown to play a key role in maintaining cell homeostasis and survival. However, the paucity of models to investigate α-SYN degradation in vivo limits our understanding of this process. Based on our recently described imaging method for measuring tau protein clearance in neurons in living zebrafish, we fused human SNCA to the photoconvertible protein Dendra2 which enabled analyses of wt and A53T α-SYN clearance kinetics in vivo. Moreover, these zebrafish models can be used to investigate the kinetics of α-SYN aggregation and to study the mechanisms, and potential new targets, controlling the clearance of both soluble and aggregated α-SYN.

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Mizuno, Yoshikuni, Nobutaka Hattori, Shin-ichiro Kubo, Shigeto Sato, Kenya Nishioka, Taku Hatano, Hiroyuki Tomiyama, Manabu Funayama, Yutaka Machida, and Hideki Mochizuki. "Progress in the pathogenesis and genetics of Parkinson's disease." Philosophical Transactions of the Royal Society B: Biological Sciences 363, no. 1500 (April 15, 2008): 2215–27. http://dx.doi.org/10.1098/rstb.2008.2273.

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Recent progresses in the pathogenesis of sporadic Parkinson's disease (PD) and genetics of familial PD are reviewed. There are common molecular events between sporadic and familial PD, particularly between sporadic PD and PARK1 -linked PD due to α - synuclein ( SNCA ) mutations. In sporadic form, interaction of genetic predisposition and environmental factors is probably a primary event inducing mitochondrial dysfunction and oxidative damage resulting in oligomer and aggregate formations of α-synuclein. In PARK1 -linked PD, mutant α-synuclein proteins initiate the disease process as they have increased tendency for self-aggregation. As highly phosphorylated aggregated proteins are deposited in nigral neurons in PD, dysfunctions of proteolytic systems, i.e. the ubiquitin–proteasome system and autophagy–lysosomal pathway, seem to be contributing to the final neurodegenerative process. Studies on the molecular mechanisms of nigral neuronal death in familial forms of PD will contribute further on the understanding of the pathogenesis of sporadic PD.

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Li, Yue, Yi Yuan, Yitong Li, Dengyang Han, Taotao Liu, Ning Yang, Xinning Mi, et al. "Inhibition of α-Synuclein Accumulation Improves Neuronal Apoptosis and Delayed Postoperative Cognitive Recovery in Aged Mice." Oxidative Medicine and Cellular Longevity 2021 (May 28, 2021): 1–21. http://dx.doi.org/10.1155/2021/5572899.

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Delayed neurocognitive recovery (dNCR) is a major complication after anesthesia and surgery in older adults. Alpha-synuclein (α-syn; encoded by the gene, SNCA) has recently been shown to play an important role in hippocampus-dependent working memory. Aggregated forms of α-syn are associated with multiple neurotoxic mechanisms, such as mitochondrial dysfunction and cell death. In this study, we found that blocking α-syn improved both mitochondrial function and mitochondria-dependent neuronal apoptosis in a mouse model of dNCR. Various forms of α-syn (including total α-syn, phosphorylated-Ser129-α-syn, and oligomers) were upregulated in hippocampal tissue and extracted mitochondria after surgical challenge. Clenbuterol is a novel transcription modulator of Scna. Clenbuterol significantly attenuated surgery-induced progressive accumulation of various toxic α-syn forms in the hippocampus, as well as mitochondrial damage and memory deficits in aged mice following surgery. We also observed excessive mitochondrial α-syn accumulation and increased mitochondria-mediated apoptosis in vitro using nerve growth factor-differentiated PC12 cells and primary hippocampal neurons exposed to lipopolysaccharide. To further validate the neuroprotective effect of α-syn inhibition, we used a lentiviral Snca-shRNA (Lv-shSnca) to knockdown Snca. Of note, Lv-shSnca transfection significantly inhibited neuronal apoptosis mediated by the mitochondrial apoptosis pathway in neurons exposed to lipopolysaccharide. This α-syn inhibition improved the disruption to mitochondrial morphology and function, as well as decreased levels of apoptosis. Our results suggest that targeting pathological α-syn may achieve neuroprotection through regulation of mitochondrial homeostasis and suppression of apoptosis in the aged hippocampus, further strengthening the therapeutic potential of targeting α-syn for dNCR.

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Suresh, S. N., Aravinda K. Chavalmane, Vidyadhara DJ, Haorei Yarreiphang, Shashank Rai, Abhik Paul, James P. Clement, Phalguni Anand Alladi, and Ravi Manjithaya. "A novel autophagy modulator 6-Bio ameliorates SNCA/α-synuclein toxicity." Autophagy 13, no. 7 (June 20, 2017): 1221–34. http://dx.doi.org/10.1080/15548627.2017.1302045.

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Sheng, Yu-Lan, Xing Chen, Xiao-Ou Hou, Xin Yuan, Bao-Shi Yuan, Yu-Qing Yuan, Qi-Lin Zhang, et al. "Urate promotes SNCA/α-synuclein clearance via regulating mTOR-dependent macroautophagy." Experimental Neurology 297 (November 2017): 138–47. http://dx.doi.org/10.1016/j.expneurol.2017.08.007.

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Poehler, Anne-Maria, Wei Xiang, Philipp Spitzer, Verena Elisabeth Luise May, Holger Meixner, Edward Rockenstein, Oldriska Chutna, et al. "Autophagy modulates SNCA/α-synuclein release, thereby generating a hostile microenvironment." Autophagy 10, no. 12 (October 30, 2014): 2171–92. http://dx.doi.org/10.4161/auto.36436.

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Lassen, Louise Berkhoudt, Maj Schneider Thomsen, Elisa Basso, Ernst-Martin Füchtbauer, Annette Füchtbauer, Tiago Fleming Outeiro, Poul Henning Jensen, and Torben Moos. "Mutation of Tyrosine Sites in the Human Alpha-Synuclein Gene Induces Neurotoxicity in Transgenic Mice with Soluble Alpha-Synuclein Oligomer Formation." Cells 11, no. 22 (November 18, 2022): 3673. http://dx.doi.org/10.3390/cells11223673.

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Overexpression of α-synuclein with tyrosine mutated to phenylalanine at position 125 leads to a severe phenotype with motor impairment and neuropathology in Drosophila. Here, we hypothesized that tyrosine mutations would similarly lead to impaired motor performance with neuropathology in a rodent model. In transgenic mice (ASO), tyrosines at positions 125, 133, and 136 in human α-synuclein were mutated to phenylalanine and cloned into a Thy1.2 expression vector, which was used to create transgenic mouse lines on a mixed genetic background TgN(Thy-1-SNCA-YF)4Emfu (YF). The YF mice had a decreased lifespan and displayed a dramatic motor phenotype with paralysis of both hind- and forelegs. Post-translational modification of α-synuclein due to phosphorylation of serine 129 is often seen in inclusions in the brains of patients with α-synucleinopathies. We observed a slight but significant increase in phosphorylation of serine 129 in the cytosol in YF mice compared to age-matched human α-synuclein transgenic mice (ASO). Conversely, significantly decreased phosphorylation of serine 129 was seen in synaptosomes of YF mice that also contained higher amounts of soluble oligomers. YF mice deposited full-length α-synuclein aggregates in neurons widespread in the CNS with the main occurrence in the forebrain structures of the cerebral cortex, the basal ganglia, and limbic structures. Full-length α-synuclein labeling was also prominent in many nuclear regions of the brain stem, deep cerebellar nuclei, and cerebellar cortex. The study shows that the substitution of tyrosines to phenylalanine in α-synuclein at positions 125, 133, and 136 leads to severe toxicity in vivo. An insignificant change upon tyrosine substitution suggests that the phosphorylation of serine 129 is not the cause of the toxicity.

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Song, Ju-Xian, Jia-Hong Lu, Liang-Feng Liu, Lei-Lei Chen, Siva Sundara Kumar Durairajan, Zhenyu Yue, Hong-Qi Zhang, and Min Li. "HMGB1 is involved in autophagy inhibition caused by SNCA/α-synuclein overexpression." Autophagy 10, no. 1 (January 1, 2013): 144–54. http://dx.doi.org/10.4161/auto.26751.

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Deng, Hao, Wenjie Xie, Yi Guo, Weidong Le, and Joseph Jankovic. "Gene dosage analysis of α-synuclein (SNCA) in patients with Parkinson's disease." Movement Disorders 21, no. 5 (May 2006): 728–29. http://dx.doi.org/10.1002/mds.20860.

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Ryskalin, Larisa, Rosangela Ferese, Gabriele Morucci, Francesca Biagioni, Carla L. Busceti, Fabrizio Michetti, Paola Lenzi, Alessandro Frati, and Francesco Fornai. "Occurrence of Total and Proteinase K-Resistant Alpha-Synuclein in Glioblastoma Cells Depends on mTOR Activity." Cancers 14, no. 6 (March 8, 2022): 1382. http://dx.doi.org/10.3390/cancers14061382.

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Alpha-synuclein (α-syn) is a protein considered to be detrimental in a number of degenerative disorders (synucleinopathies) of which α-syn aggregates are considered a pathological hallmark. The clearance of α-syn strongly depends on autophagy, which can be stimulated by inhibiting the mechanistic target of rapamycin (mTOR). Thus, the overexpression of mTOR and severe autophagy suppression may produce α-syn accumulation, including the proteinase K-resistant protein isoform. Glioblastoma multiforme (GBM) is a lethal brain tumor that features mTOR overexpression and severe autophagy inhibition. Cell pathology in GBM is reminiscent of a fast, progressive degenerative disorder. Therefore, the present work questions whether, as is analogous to neurons during degenerative disorders, an overexpression of α-syn occurs within GBM cells. A high amount of α-syn was documented in GBM cells via real-time PCR (RT-PCR), Western blotting, immunohistochemistry, immuno-fluorescence, and ultrastructural stoichiometry, compared with the amount of β- and γ-synucleins and compared with the amount of α-syn counted within astrocytes. The present study indicates that (i) α-syn is overexpressed in GBM cells, (ii) α-syn expression includes a proteinase-K resistant isoform, (iii) α-syn is dispersed from autophagy-like vacuoles to the cytosol, (iv) α-syn overexpression and cytosol dispersion are mitigated by rapamycin, and (v) the α-syn-related GBM-like phenotype is mitigated by silencing the SNCA gene.

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Gajendran, Nithya, Santhanasabapathy Rajasekaran, Nirjhar M. Aloy, Sahar Shekoohi, and Stephan N. Witt. "Abstract 2443: Knocking out SNCA in SKMEL28 melanoma cells suppresses EMT and prevents invasion." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2443. http://dx.doi.org/10.1158/1538-7445.am2022-2443.

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Abstract Malignant melanoma is one of the most aggressive and fifth most prevalent cancer among men and women. Clinical and epidemiological studies shows that Parkinson’s disease (PD) patients have higher risk of developing invasive melanoma, and, reciprocally, patients with invasive melanoma have a higher risk of developing PD. Alpha-synuclein (α-syn; SNCA), an intrinsically disordered protein expressed in neurons, is also highly expressed in malignant melanoma and is a common molecular signature between Parkinson’s disease and melanoma. We have previously reported that SK-Mel-28 SNCA-knockout (KO) cells exhibit suppressed tumor growth and proliferation in vivo and in vitro, and that putting back SNCA via lenti virus restored the phenotype to that of the control cells. The present study is designed to investigate the role of α-syn in melanoma progression in SK-MEL-28 cells in the context of metastasis and the epithelial-to-mesenchymal transition (EMT). The SK-Mel-28 SNCA-KO clones showed a significant decrease in the cell-surface protein L1CAM, a major cell adhesion molecule highly expressed in various melanoma and correlates with melanoma progression, whereas the knock in clones resembled the control. Migration and invasion assay were performed using transwell chambers showed a profound migratory and invasive defect in SNCA-KO clones. To explore further whether this is a proliferative or migratory defect, a single cell phagokinetic motility assay was performed with colloidal gold which showed a marked decrease in cell motility in knockout clones compared to control and knock in clones, which was consistent with our migration and invasion experiments. To determine the proteins involved in the inhibition of invasion mediated by α-syn, we immunoblotted for the mesenchymal markers N-cadherin and vimentin, and these were significantly downregulated in the SNCA-KO clones. These data reinforce that knocking out SNCA impedes melanoma cell migration and invasion in SK-Mel- 28 cell line, implying that α-syn might be a novel therapeutic target for malignant melanoma. Citation Format: Nithya Gajendran, Santhanasabapathy Rajasekaran, Nirjhar M. Aloy, Sahar Shekoohi, Stephan N. Witt. Knocking out SNCA in SKMEL28 melanoma cells suppresses EMT and prevents invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2443.

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Hoppe, Simon Oliver, Gamze Uzunoğlu, and Carmen Nussbaum-Krammer. "α-Synuclein Strains: Does Amyloid Conformation Explain the Heterogeneity of Synucleinopathies?" Biomolecules 11, no. 7 (June 23, 2021): 931. http://dx.doi.org/10.3390/biom11070931.

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Synucleinopathies are a heterogeneous group of neurodegenerative diseases with amyloid deposits that contain the α-synuclein (SNCA/α-Syn) protein as a common hallmark. It is astonishing that aggregates of a single protein are able to give rise to a whole range of different disease manifestations. The prion strain hypothesis offers a possible explanation for this conundrum. According to this hypothesis, a single protein sequence is able to misfold into distinct amyloid structures that can cause different pathologies. In fact, a growing body of evidence suggests that conformationally distinct α-Syn assemblies might be the causative agents behind different synucleinopathies. In this review, we provide an overview of research on the strain hypothesis as it applies to synucleinopathies and discuss the potential implications for diagnostic and therapeutic purposes.

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Er, Safak. "Snca-GFP Knock-In Mice Allows Tracking the Endogenous α-Synuclein in Action." eneuro 8, no. 1 (January 2021): ENEURO.0544–20.2021. http://dx.doi.org/10.1523/eneuro.0544-20.2021.

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Du, Ting-Ting, Le Wang, Chun-Li Duan, Ling-Ling Lu, Jian-Liang Zhang, Ge Gao, Xiao-Bo Qiu, Xiao-Min Wang, and Hui Yang. "GBA deficiency promotes SNCA/α-synuclein accumulation through autophagic inhibition by inactivated PPP2A." Autophagy 11, no. 10 (October 3, 2015): 1803–20. http://dx.doi.org/10.1080/15548627.2015.1086055.

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Cao, Yu-Lan, Ya-Ping Yang, Cheng-Jie Mao, Xiao-Qi Zhang, Chen-Tao Wang, Jing Yang, Dong-Jun Lv, Fen Wang, Li-Fang Hu, and Chun-Feng Liu. "A role of BAG3 in regulating SNCA/α-synuclein clearance via selective macroautophagy." Neurobiology of Aging 60 (December 2017): 104–15. http://dx.doi.org/10.1016/j.neurobiolaging.2017.08.023.

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Esteves, A. Raquel, and Sandra M. Cardoso. "LRRK2 at the Crossroad Between Autophagy and Microtubule Trafficking." Neuroscientist 23, no. 1 (July 8, 2016): 16–26. http://dx.doi.org/10.1177/1073858415616558.

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Mutations in leucine-rich repeat kinase 2 ( lrrk2) gene cause inherited Parkinson’s disease (PD), and common variants in lrrk2 are a risk factor for sporadic PD. The neuropathology associated with LRRK2-linked PD is extremely pleomorphic involving inclusions of α-synuclein (SNCA), tau or neither, therefore suggesting that LRRK2 may be central in the pathogenic pathways of PD. This large protein localizes in the cytosol, as well as, in specific membrane domains, including mitochondria and autophagosomes and interacts with a wide range of proteins such as SNCA, tau, α- and β-tubulin. For this reason LRRK2 has been associated with a variety of cellular functions, including autophagy, mitochondrial function/dynamics and microtubule/cytoskeletal dynamics. LRRK2 has been shown to interact with microtubules as well as with mitochondria interfering with their network and dynamics. Moreover, LRRK2 knock-out or mutations affect autophagic efficiency. Here, we review and discuss the literature on how LRRK2 affects mitochondrial function, autophagy, and microtubule dynamics and how this is implicated in the PD etiology.

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Sampedro, Frederic, Juan Marín-Lahoz, Saul Martínez-Horta, Javier Pagonabarraga, and Jaime Kulisevsky. "Cortical Thinning Associated with Age and CSF Biomarkers in Early Parkinson’s Disease Is Modified by the SNCA rs356181 Polymorphism." Neurodegenerative Diseases 18, no. 5-6 (2018): 233–38. http://dx.doi.org/10.1159/000493103.

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The role of cerebrospinal fluid (CSF) biomarkers such as CSF α-synuclein and CSF tau in predicting cognitive decline in Parkinson’s disease (PD) continues to be inconsistent. Here, using a cohort of de novo PD patients with preserved cognition from the Parkinson’s Progression Markers Initiative (PPMI), we show that the SNCA rs356181 single nucleotide polymorphism (SNP) modulates the effect of these CSF biomarkers on cortical thinning. Depending on this SNP’s genotype, cortical atrophy was associated with either higher or lower CSF biomarker levels. Additionally, this SNP modified age-related atrophy. Importantly, the integrity of the brain regions where this phenomenon was observed correlated with cognitive measures. These results suggest that this genetic variation of the gene encoding the α-synuclein protein, known to be involved in the development of PD, also interferes in its subsequent neurodegeneration. Overall, our findings could shed light on the so far incongruent association of common CSF biomarkers with cognitive decline in PD.

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Xia, Yuxing, Grace M. Lloyd, and Benoit I. Giasson. "Targeted proteolytic products of τ and α-synuclein in neurodegeneration." Essays in Biochemistry 65, no. 7 (December 2021): 905–12. http://dx.doi.org/10.1042/ebc20210028.

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Abstract CNS pathological inclusions comprising τ or α-synuclein (αSyn) define a spectrum of neurodegenerative diseases, and these can often present concurrently in the same individuals. The aggregation of both proteins is clearly associated with neurodegeneration and the deleterious properties of each protein is further supported by mutations in each gene (MAPT and SNCA, respectively) resulting in disease. The initiating events in most sporadic neurodegenerative diseases are still unclear but growing evidence suggests that the aberrant proteolytic cleavage of τ and αSyn results in products that can be toxic and/or initiate aggregation that can further spread by a prion-like mechanism. The accumulation of some of these cleavage products can further potentiate the progression of protein aggregation transmission and lead to their accumulation in peripheral biofluids such as cerebrospinal fluid (CSF) and blood. The future development of new tools to detect specific τ and αSyn abnormal cleavage products in peripheral biofluids could be useful biomarkers and better understand of the role of unique proteolytic activities could yield therapeutic interventions.

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Angelova, Plamena R., Minee L. Choi, Alexey V. Berezhnov, Mathew H. Horrocks, Craig D. Hughes, Suman De, Margarida Rodrigues, et al. "Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation." Cell Death & Differentiation 27, no. 10 (April 27, 2020): 2781–96. http://dx.doi.org/10.1038/s41418-020-0542-z.

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Abstract Protein aggregation and abnormal lipid homeostasis are both implicated in neurodegeneration through unknown mechanisms. Here we demonstrate that aggregate-membrane interaction is critical to induce a form of cell death called ferroptosis. Importantly, the aggregate-membrane interaction that drives ferroptosis depends both on the conformational structure of the aggregate, as well as the oxidation state of the lipid membrane. We generated human stem cell-derived models of synucleinopathy, characterized by the intracellular formation of α-synuclein aggregates that bind to membranes. In human iPSC-derived neurons with SNCA triplication, physiological concentrations of glutamate and dopamine induce abnormal calcium signaling owing to the incorporation of excess α-synuclein oligomers into membranes, leading to altered membrane conductance and abnormal calcium influx. α-synuclein oligomers further induce lipid peroxidation. Targeted inhibition of lipid peroxidation prevents the aggregate-membrane interaction, abolishes aberrant calcium fluxes, and restores physiological calcium signaling. Inhibition of lipid peroxidation, and reduction of iron-dependent accumulation of free radicals, further prevents oligomer-induced toxicity in human neurons. In summary, we report that peroxidation of polyunsaturated fatty acids underlies the incorporation of β-sheet-rich aggregates into the membranes, and that additionally induces neuronal death. This suggests a role for ferroptosis in Parkinson’s disease, and highlights a new mechanism by which lipid peroxidation causes cell death.

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Sokratous, Maria, Marianthi Breza, Konstantin Senkevich, Ziv Gan‐Or, Stefania Kalampokini, Cleanthi Spanaki, Antonios Provatas, et al. "α‐Synuclein ( SNCA ) A30G Mutation as a Cause of a Complex Phenotype Without Parkinsonism." Movement Disorders 36, no. 9 (September 2021): 2209–12. http://dx.doi.org/10.1002/mds.28735.

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Al-Chalabi, Ammar, Alexandra Dürr, Nicholas W. Wood, Michael H. Parkinson, Agnes Camuzat, Jean-Sébastien Hulot, Karen E. Morrison, et al. "Genetic Variants of the α-Synuclein Gene SNCA Are Associated with Multiple System Atrophy." PLoS ONE 4, no. 9 (September 22, 2009): e7114. http://dx.doi.org/10.1371/journal.pone.0007114.

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Sampaio-Marques, Belém, Carolina Felgueiras, Alexandra Silva, Márcio Rodrigues, Sandra Tenreiro, Vanessa Franssens, Andreas S. Reichert, Tiago F. Outeiro, Joris Winderickx, and Paula Ludovico. "SNCA (α-synuclein)-induced toxicity in yeast cells is dependent on Sir2-mediated mitophagy." Autophagy 8, no. 10 (October 16, 2012): 1494–509. http://dx.doi.org/10.4161/auto.21275.

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McCarthy, Erin, Aaron Barron, Noelia Morales-Prieto, Martina Mazzocchi, Cathal M. McCarthy, Louise M. Collins, Aideen M. Sullivan, and Gerard W. O’Keeffe. "Gene Co-expression Analysis of the Human Substantia Nigra Identifies ZNHIT1 as an SNCA Co-expressed Gene that Protects Against α-Synuclein-Induced Impairments in Neurite Growth and Mitochondrial Dysfunction in SH-SY5Y Cells." Molecular Neurobiology 59, no. 5 (February 17, 2022): 2745–57. http://dx.doi.org/10.1007/s12035-022-02768-9.

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AbstractParkinson’s disease (PD) is neurodegenerative disorder with the pathological hallmarks of progressive degeneration of midbrain dopaminergic neurons from the substantia nigra (SN), and accumulation and spread of inclusions of aggregated α-synuclein (α-Syn). Since current PD therapies do not prevent neurodegeneration, there is a need to identify therapeutic targets that can prevent α-Syn-induced reductions in neuronal survival and neurite growth. We hypothesised that genes that are normally co-expressed with the α-Syn gene (SNCA), and whose co-expression pattern is lost in PD, may be important for protecting against α-Syn-induced dopaminergic degeneration, since broken correlations can be used as an index of functional misregulation. Gene co-expression analysis of the human SN showed that nuclear zinc finger HIT-type containing 1 (ZNHIT1) is co-expressed with SNCA and that this co-expression pattern is lost in PD. Overexpression of ZNHIT1 was found to increase deposition of the H2A.Z histone variant in SH-SY5Y cells, to promote neurite growth and to prevent α-Syn-induced reductions in neurite growth and cell viability. Analysis of ZNHIT1 co-expressed genes showed significant enrichment in genes associated with mitochondrial function. In agreement, bioenergetic state analysis of mitochondrial function revealed that ZNHIT1 increased cellular ATP synthesis. Furthermore, α-Syn-induced impairments in basal respiration, maximal respiration and spare respiratory capacity were not seen in ZNHIT1-overexpressing cells. These data show that ZNHIT1 can protect against α-Syn-induced degeneration and mitochondrial dysfunction, which rationalises further investigation of ZNHIT1 as a therapeutic target for PD.

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Brazdis, Razvan-Marius, Julian E. Alecu, Daniel Marsch, Annika Dahms, Katrin Simmnacher, Sandra Lörentz, Anna Brendler, et al. "Demonstration of brain region-specific neuronal vulnerability in human iPSC-based model of familial Parkinson’s disease." Human Molecular Genetics 29, no. 7 (March 11, 2020): 1180–91. http://dx.doi.org/10.1093/hmg/ddaa039.

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Abstract Parkinson’s disease (PD) is a neurodegenerative disorder characterized by protein inclusions mostly composed of aggregated forms of α-synuclein (α-Syn) and by the progressive degeneration of midbrain dopaminergic neurons (mDANs), resulting in motor symptoms. While other brain regions also undergo pathologic changes in PD, the relevance of α-Syn aggregation for the preferential loss of mDANs in PD pathology is not completely understood yet. To elucidate the mechanisms of the brain region-specific neuronal vulnerability in PD, we modeled human PD using human-induced pluripotent stem cells (iPSCs) from familial PD cases with a duplication (Dupl) of the α-Syn gene (SNCA) locus. Human iPSCs from PD Dupl patients and a control individual were differentiated into mDANs and cortical projection neurons (CPNs). SNCA dosage increase did not influence the differentiation efficiency of mDANs and CPNs. However, elevated α-Syn pathology, as revealed by enhanced α-Syn insolubility and phosphorylation, was determined in PD-derived mDANs compared with PD CPNs. PD-derived mDANs exhibited higher levels of reactive oxygen species and protein nitration levels compared with CPNs, which might underlie elevated α-Syn pathology observed in mDANs. Finally, increased neuronal death was observed in PD-derived mDANs compared to PD CPNs and to control mDANs and CPNs. Our results reveal, for the first time, a higher α-Syn pathology, oxidative stress level, and neuronal death rate in human PD mDANs compared with PD CPNs from the same patient. The finding implies the contribution of pathogenic α-Syn, probably induced by oxidative stress, to selective vulnerability of substantia nigra dopaminergic neurons in human PD.

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Rutherford, Nicola J., Brenda D. Moore, Todd E. Golde, and Benoit I. Giasson. "Divergent effects of the H50Q and G51D SNCA mutations on the aggregation of α-synuclein." Journal of Neurochemistry 131, no. 6 (July 21, 2014): 859–67. http://dx.doi.org/10.1111/jnc.12806.

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Journal articles on the topic 'Α-Synuclein (SNCA)'

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