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Journal articles on the topic 'Alpha synuclein'

Author: Grafiati
Published: 4 June 2021
Last updated: 21 December 2024

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1

Hasegawa, M. "Alpha-Synuclein." Journal of the Neurological Sciences 381 (October 2017): 29. http://dx.doi.org/10.1016/j.jns.2017.08.126.

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2

Vasili, Eftychia, Antonio Dominguez-Meijide, Manuel Flores-León, Mohammed Al-Azzani, Angeliki Kanellidi, Ronald Melki, Leonidas Stefanis, and Tiago Fleming Outeiro. "Endogenous Levels of Alpha-Synuclein Modulate Seeding and Aggregation in Cultured Cells." Molecular Neurobiology 59, no. 2 (January 4, 2022): 1273–84. http://dx.doi.org/10.1007/s12035-021-02713-2.

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AbstractParkinson’s disease is a progressive neurodegenerative disorder characterized by the accumulation of misfolded alpha-synuclein in intraneuronal inclusions known as Lewy bodies and Lewy neurites. Multiple studies strongly implicate the levels of alpha-synuclein as a major risk factor for the onset and progression of Parkinson’s disease. Alpha-synuclein pathology spreads progressively throughout interconnected brain regions but the precise molecular mechanisms underlying the seeding of alpha-synuclein aggregation are still unclear. Here, using stable cell lines expressing alpha-synuclein, we examined the correlation between endogenous alpha-synuclein levels and the seeding propensity by exogenous alpha-synuclein preformed fibrils. We applied biochemical approaches and imaging methods in stable cell lines expressing alpha-synuclein and in primary neurons to determine the impact of alpha-synuclein levels on seeding and aggregation. Our results indicate that the levels of alpha-synuclein define the pattern and severity of aggregation and the extent of p-alpha-synuclein deposition, likely explaining the selective vulnerability of different cell types in synucleinopathies. The elucidation of the cellular processes involved in the pathological aggregation of alpha-synuclein will enable the identification of novel targets and the development of therapeutic strategies for Parkinson’s disease and other synucleinopathies.
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3

Shameli, Afshin, Wenbin Xiao, Clifford Harding, Howard Meyerson, John Sumodi, and Robert Maitta. "Development Of Mature T Lymphocytes Requires Alpha-Synuclein." Blood 122, no. 21 (November 15, 2013): 3490. http://dx.doi.org/10.1182/blood.v122.21.3490.3490.

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Abstract Synucleins (including α-, β- and γ-synucleins) are a group of proteins that are expressed at high levels in the central nervous system. The physiologic function of these proteins is unknown. Alpha-synuclein has been implicated in the pathogenesis of neurodegenerative disorders such as Parkinson's disease and Lewy body dementia, as it is highly expressed in the Lewy bodies from both disorders. The expression of α-synuclein in hematopoietic system has been shown in erythroid precursors and megakaryocytes in bone marrow, as well as erythrocytes and platelets in peripheral blood. Moreover, some studies demonstrated the expression of α-synuclein on peripheral blood mononuclear cells (PBMC), including B and T lymphocytes, NK cells and monocytes; and its expression is shown to be higher in PBMCs of individuals with Parkinson's disease compared to healthy controls. In order to study the role of α-synuclein in development of different hematopoietic elements, we compared bone marrow, peripheral blood and lymphoid organs of age and sex-matched α-synuclein knock-out (KO) mice and wild type (WT) animals of the same genetic background (n=10). Flow cytometric analysis of bone marrow elements did not show differences in the percentages and absolute numbers of erythroid, megakryocytic and myeloid lineages (data not shown). However, differential complete blood cell count (CBC) showed statistically significant decrease in red blood cell (RBC) count, hemoglobin (Hb) and hematocrit (Hct) in KO mice compared to WT mice. No difference was noted in other RBC indices (Table 1). However, platelets were smaller in KO mice as measured by the mean platelet volume (MPV). There was no difference in the number of platelets and white blood cell (WBC) counts. There was a significant reduction in the percentage of circulating lymphocytes, and associated increase in the percentage of neutrophils and monocytes in KO mice compared to WT mice, although the difference in the number of lymphocytes did not reach statistical significance (Table 1). Flow cytometric analysis of T lymphocytes in thymus and peripheral lymphoid organs demonstrated marked defect in development of mature T cells. There was a significant increase in the number of double negative thymocytes in KO mice associated with significant decrease in the number of single positive T cells. Furthermore, splenic CD4+ and CD8+ T cells were markedly decreased in KO mice, indicating that α-synuclein is required for T cell development (Table 2). In summary, our findings indicate an absolute requirement for α-synuclein in development of mature T lymphocytes. The underlying mechanism for this function is subject of future studies. Moreover, while α-synuclein-deficiency does not affect the development of myeloid lineage and platelets, lack of this protein is associated with lower number of erythrocytes, suggesting its role in development and/or survival red blood cells. Disclosures: No relevant conflicts of interest to declare.
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4

Labrie, Viviane, and Patrik Brundin. "Alpha-Synuclein to the Rescue: Immune Cell Recruitment by Alpha-Synuclein during Gastrointestinal Infection." Journal of Innate Immunity 9, no. 5 (2017): 437–40. http://dx.doi.org/10.1159/000479653.

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Intraneuronal accumulation of misfolded alpha-synuclein in the central and peripheral nervous systems is strongly linked to Parkinson disease (PD) and other related synucleinopathies. In rare inherited forms of PD, point mutations or gene multiplications mediate the formation of alpha-synuclein protein aggregates. However, in most PD cases it is presumed that the combined effects of ageing and environmental factors drive the formation of alpha-synuclein aggregates. Despite advances regarding alpha-synuclein pathobiology, the normal functions of this protein and factors that regulate its expression are not well understood. We discuss a recent study reporting that viral infection induces alpha-synuclein expression in neurons of the gastrointestinal tract. Alpha-synuclein levels increased during norovirus infection in the duodenum of children. In an in vitro paradigm, monomeric and oligomeric alpha-synuclein acted as chemoattractants for neutrophils and monocytes, and promoted the maturation of dendritic cells. This suggests that alpha-synuclein facilitates immune responses to infection. We explore the possibility that intestinal infections, and associated inflammation, place individuals at increased risk of PD by increasing alpha-synuclein levels and promoting the formation of alpha-synuclein aggregates that propagate in a prion-like fashion via the vagal nerve to the brainstem.
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5

Goloborshcheva, Valeria V., Valerian G. Kucheryanu, Natalia A. Voronina, Ekaterina V. Teterina, Aleksey A. Ustyugov, and Sergei G. Morozov. "Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons." Biomedicines 10, no. 9 (September 14, 2022): 2278. http://dx.doi.org/10.3390/biomedicines10092278.

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Parkinson’s disease (PD) is one of the key neurodegenerative disorders caused by a dopamine deficiency in the striatum due to the death of dopaminergic (DA) neurons of the substantia nigra pars compacta. The initially discovered A53T mutation in the alpha-synuclein gene was linked to the formation of cytotoxic aggregates: Lewy bodies in the DA neurons of PD patients. Further research has contributed to the discovery of beta- and gamma-synucleins, which presumably compensate for the functional loss of either member of the synuclein family. Here, we review research from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity models and various synuclein-knockout animals. We conclude that the differences in the sensitivity of the synuclein-knockout animals compared with the MPTP neurotoxin are due to the ontogenetic selection of early neurons followed by a compensatory effect of beta-synuclein, which optimizes dopamine capture in the synapses. Triple-knockout synuclein studies have confirmed the higher sensitivity of DA neurons to the toxic effects of MPTP. Nonetheless, beta-synuclein could modulate the alpha-synuclein function, preventing its aggregation and loss of function. Overall, the use of knockout animals has helped to solve the riddle of synuclein functions, and these proteins could be promising molecular targets for the development of therapies that are aimed at optimizing the synaptic function of dopaminergic neurons.
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6

You, Xuemei, Subash C. B. Gopinath, Thangavel Lakshmipriya, and Dingan Li. "High-Affinity Detection of Alpha-Synuclein by Aptamer-Gold Conjugates on an Amine-Modified Dielectric Surface." Journal of Analytical Methods in Chemistry 2019 (November 30, 2019): 1–8. http://dx.doi.org/10.1155/2019/6526850.

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Parkinson’s disease (PD) is a progressive health issue and influences an increasingly larger number of people, especially at older ages, affecting the central nervous system (CNS). Alpha-synuclein is a biomarker closely correlated with the CNS and PD. The loss of neuronal cells in the substantia nigra leads to the aggregation of alpha-synuclein in the form of Lewy bodies, and Lewy neuritis is a neuropathological hallmark. The therapeutic approach of PD focuses on alpha-synuclein as an important substrate of PD pathology. So far, research has focused on antialpha-synuclein to minimize the burden of extracellular alpha-synuclein in the brain, and as a consequence, it ameliorates inflammation. Interdigitated electrode (IDE) biosensors are efficient tools for detecting various analytes and were chosen in this study to detect alpha-synuclein on amine-modified surfaces by using antiaptamer-alpha-synuclein as the probe. In addition, a gold nanoparticle-conjugated aptamer was used to enhance the detection limit. The limit of detection for the binding between alpha-synuclein and aptamer was found to be 10 pM. Control experiments were performed with two closely related proteins, amyloid-beta and tau, to reveal the specificity; the results show that the aptamer only recognized alpha-synuclein. The proposed strategy helps to identify the binding of aptamer and alpha-synuclein and provides a possible method to lower alpha-synuclein levels and inflammation in PD patients.
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7

Upcott, Matthew, Kirill D. Chaprov, and Vladimir L. Buchman. "Toward a Disease-Modifying Therapy of Alpha-Synucleinopathies: New Molecules and New Approaches Came into the Limelight." Molecules 26, no. 23 (December 3, 2021): 7351. http://dx.doi.org/10.3390/molecules26237351.

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The accumulation of the various products of alpha-synuclein aggregation has been associated with the etiology and pathogenesis of several neurodegenerative conditions, including both familial and sporadic forms of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). It is now well established that the aggregation and spread of alpha-synuclein aggregation pathology activate numerous pathogenic mechanisms that contribute to neurodegeneration and, ultimately, to disease progression. Therefore, the development of a safe and effective disease-modifying therapy that limits or prevents the accumulation of the toxic intermediate products of alpha-synuclein aggregation and the spread of alpha-synuclein aggregation pathology could provide significant positive clinical outcomes in PD/DLB cohorts. It has been suggested that this goal can be achieved by reducing the intracellular and/or extracellular levels of monomeric and already aggregated alpha-synuclein. The principal aim of this review is to critically evaluate the potential of therapeutic strategies that target the post-transcriptional steps of alpha-synuclein production and immunotherapy-based approaches to alpha-synuclein degradation in PD/DLB patients. Strategies aimed at the downregulation of alpha-synuclein production are at an early preclinical stage of drug development and, although they have shown promise in animal models of alpha-synuclein aggregation, many limitations need to be resolved before in-human clinical trials can be seriously considered. In contrast, many strategies aimed at the degradation of alpha-synuclein using immunotherapeutic approaches are at a more advanced stage of development, with some in-human Phase II clinical trials currently in progress. Translational barriers for both strategies include the limitations of alpha-synuclein aggregation models, poor understanding of the therapeutic window for the alpha-synuclein knockdown, and variability in alpha-synuclein pathology across patient cohorts. Overcoming such barriers should be the main focus of further studies. However, it is already clear that these strategies do have the potential to achieve a disease-modifying effect in PD and DLB.
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8

Yamada, Masahito. "3) ^|^alpha;-Synuclein, ^|^alpha;-synucleinopathies, and Dementia." Nihon Naika Gakkai Zasshi 100, no. 9 (2011): 2476–81. http://dx.doi.org/10.2169/naika.100.2476.

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9

Yamada, Masahito. "3) ^|^alpha;-Synuclein, ^|^alpha;-synucleinopathies, and Dementia." Nihon Naika Gakkai Zasshi 100, Suppl (2011): 73b. http://dx.doi.org/10.2169/naika.100.73b.

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10

Shavali, Shaik, Holly M. Brown-Borg, Manuchair Ebadi, and James Porter. "Mitochondrial localization of alpha-synuclein protein in alpha-synuclein overexpressing cells." Neuroscience Letters 439, no. 2 (July 2008): 125–28. http://dx.doi.org/10.1016/j.neulet.2008.05.005.

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11

Andoskin, P. A., A. K. Emelyanov, M. A. Nikolaev, K. A. Senkevich, V. P. Shilin, A. F. Yakimovskiy, A. A. Timofeeva, and S. N. Pchelina. "Parkinson's disease (PD) is the most common neurodegenerative disease." Scientific Notes of the I. P. Pavlov St. Petersburg State Medical University 22, no. 2 (June 30, 2015): 14–17. http://dx.doi.org/10.24884/1607-4181-2015-22-2-14-17.

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Metabolic impairment of alpha-synuclein protein is considered to be the central event in PDpathogenesis. Recent studies explored usage of alpha-synuclein in peripheral fluids as a biomarker of PD, however alpha-synuclein level in the CSF and plasma is considered to be affected by hemolysis. In order to avoid contamination of a lymphocyte fraction by erythrocytes, we have proposed an algorithm based on measurements of alpha-synuclein levels in the homogeneous CD45+ cell blood fraction. For this study we formed a group of PD patients (N=14) and a control group without the neurological disorders (N=17). We found an increase in the level of the total alpha-synuclein in CD45+ cells of PD patients compared to controls (p = 0,04), and revealed a direct correlation between the level of dopamine in plasma and level of total alpha-synuclein in CD45+ cells in the control group (r=0,71, p = 0,007).The level of alpha-synuclein in CD45+ cells could be suggested as possible PD biomarker.
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12

Lilamand, Matthieu, Josué Clery, Agathe Vrillon, François Mouton-Liger, Emmanuel Cognat, Sinead Gaubert, Claire Hourregue, et al. "Cerebrospinal Fluid Alpha-Synuclein Improves the Differentiation between Dementia with Lewy Bodies and Alzheimer’s Disease in Clinical Practice." International Journal of Molecular Sciences 23, no. 21 (November 4, 2022): 13488. http://dx.doi.org/10.3390/ijms232113488.

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Background: Alpha-synuclein, abnormally aggregated in Dementia with Lewy Bodies (DLB), could represent a potential biomarker to improve the differentiation between DLB and Alzheimer’s disease (AD). Our main objective was to compare Cerebrospinal Fluid (CSF) alpha-synuclein levels between patients with DLB, AD and Neurological Control (NC) individuals. Methods: In a monocentric retrospective study, we assessed CSF alpha-synuclein concentration with a validated ELISA kit (ADx EUROIMMUN) in patients with DLB, AD and NC from a tertiary memory clinic. Between-group comparisons were performed, and Receiver Operating Characteristic analysis was used to identify the best CSF alpha-synuclein threshold. We examined the associations between CSF alpha-synuclein, other core AD CSF biomarkers and brain MRI characteristics. Results: We included 127 participants (mean age: 69.3 ± 8.1, Men: 41.7%). CSF alpha-synuclein levels were significantly lower in DLB than in AD (1.28 ± 0.52 ng/mL vs. 2.26 ± 0.91 ng/mL, respectively, p < 0.001) without differences due to the stage of cognitive impairment. The best alpha-synuclein threshold was characterized by an Area Under the Curve = 0.85, Sensitivity = 82.0% and Specificity = 76.0%. CSF alpha-synuclein was associated with CSF AT(N) biomarkers positivity (p < 0.01) but not with hippocampal atrophy or white matter lesions. Conclusion: CSF Alpha-synuclein evaluation could help to early differentiate patients with DLB and AD in association with existing biomarkers.
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13

Izco, Maria, Martin Schleef, Marco Schmeer, Estefania Carlos, Guglielmo Verona, and Lydia Alvarez-Erviti. "Targeted Extracellular Vesicle Gene Therapy for Modulating Alpha-Synuclein Expression in Gut and Spinal Cord." Pharmaceutics 15, no. 4 (April 13, 2023): 1230. http://dx.doi.org/10.3390/pharmaceutics15041230.

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The development of effective disease-modifying therapies to halt Parkinson’s disease (PD) progression is required. In a subtype of PD patients, alpha-synuclein pathology may start in the enteric nervous system (ENS) or autonomic peripheral nervous system. Consequently, strategies to decrease the expression of alpha-synuclein in the ENS will be an approach to prevent PD progression at pre-clinical stages in these patients. In the present study, we aimed to assess if anti-alpha-synuclein shRNA-minicircles (MC) delivered by RVG-extracellular vesicles (RVG-EV) could downregulate alpha-synuclein expression in the intestine and spinal cord. RVG-EV containing shRNA-MC were injected intravenously in a PD mouse model, and alpha-synuclein downregulation was evaluated by qPCR and Western blot in the cord and distal intestine. Our results confirmed the downregulation of alpha-synuclein in the intestine and spinal cord of mice treated with the therapy. We demonstrated that the treatment with anti-alpha-synuclein shRNA-MC RVG-EV after the development of pathology is effective to downregulate alpha-synuclein expression in the brain as well as in the intestine and spinal cord. Moreover, we confirmed that a multidose treatment is necessary to maintain downregulation for long-term treatments. Our results support the potential use of anti-alpha-synuclein shRNA-MC RVG-EV as a therapy to delay or halt PD pathology progression.
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14

Gonzalez-Horta, Azucena. "The Interaction of Alpha-synuclein with Membranes and its Implication in Parkinson's Disease: A Literature Review." Natural Product Communications 10, no. 10 (October 2015): 1934578X1501001. http://dx.doi.org/10.1177/1934578x1501001034.

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Alpha-synuclein belongs to the class of intrinsically disordered proteins lacking a well-folded structure under physiological conditions. The conversion of alpha-synuclein from a soluble monomer to an insoluble fibril may underlie the neurodegeneration associated with Parkinson's disease (PD). Although the exact mechanism of alpha-synuclein toxicity is still unknown, it has been proposed that alpha-synuclein disturbs membrane structure, leading to increased membrane permeability and eventual cell death. This review highlights the significant role played by fluorescence techniques in unraveling the nature of interactions between alpha-synuclein and membranes and its implications in PD.
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15

Vorobyov, Vasily, Alexander Deev, Iuliia Sukhanova, Olga Morozova, Zoya Oganesyan, Kirill Chaprov, and Vladimir L. Buchman. "Loss of the Synuclein Family Members Differentially Affects Baseline- and Apomorphine-Associated EEG Determinants in Single-, Double- and Triple-Knockout Mice." Biomedicines 10, no. 12 (December 4, 2022): 3128. http://dx.doi.org/10.3390/biomedicines10123128.

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Synucleins comprise a family of small proteins highly expressed in the nervous system of vertebrates and involved in various intraneuronal processes. The malfunction of alpha-synuclein is one of the key events in pathogenesis of Parkinson disease and certain other neurodegenerative diseases, and there is a growing body of evidence that malfunction of other two synucleins might be involved in pathological processes in the nervous system. The modulation of various presynaptic mechanisms of neurotransmission is an important function of synucleins, and therefore, it is feasible that their deficiency might affect global electrical activity detected of the brain. However, the effects of the loss of synucleins on the frequency spectra of electroencephalograms (EEGs) have not been systematically studied so far. In the current study, we assessed changes in such spectra in single-, double- and triple-knockout mice lacking alpha-, beta- and gamma-synucleins in all possible combinations. EEGs were recorded from the motor cortex, the putamen, the ventral tegmental area and the substantia nigra of 78 3-month-old male mice from seven knockout groups maintained on the C57BL/6J genetic background, and 10 wild-type C57BL/6J mice for 30 min before and for 60 min after the systemic injection of a DA receptor agonist, apomorphine (APO). We found that almost any variant of synuclein deficiency causes multiple changes in both basal and APO-induced EEG oscillation profiles. Therefore, it is not the absence of any particular synuclein but rather a disbalance of synucleins that causes widespread changes in EEG spectral profiles.
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16

Liu, Xiaoguang, Kaluvu Balaraman, Ciarán C. Lynch, Michaeline Hebron, Priya Ketankumar Shah, Shicheng Hu, Max Stevenson, Christian Wolf, and Charbel Moussa. "Inhibition of Ubiquitin-Specific Protease-13 Improves Behavioral Performance in Alpha-Synuclein Expressing Mice." International Journal of Molecular Sciences 23, no. 15 (July 23, 2022): 8131. http://dx.doi.org/10.3390/ijms23158131.

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Ubiquitin-Specific Protease-13 (USP13) promotes protein de-ubiquitination. USP13 levels are upregulated in post-mortem Parkinson’s disease, whereas USP13 knockdown via shRNA reduces alpha-synuclein levels in animal models. We studied the role of USP13 in knockout mice expressing lentiviral human alpha-synuclein and investigated the impact of a small molecule inhibitor of USP13, BK50118-C, on alpha-synuclein pathology and animal behavior. Alpha-synuclein was expressed unilaterally in substantia nigra (SN) of USP13 deficient mice that were treated with a daily intraperitoneal injection of 100 mg/kg BK50118-C or DMSO for four consecutive weeks, and behavioral and functional assays were performed. Wild-type USP13+/+ mice expressing lentiviral human alpha-synuclein showed motor and behavioral defects that were not seen in partially (USP13+/−) or completely (USP13−/−) deficient USP13 mice. BK50118-C displayed a wide and favorable therapeutic dose range in vivo. Treatment with BK50118-C significantly reduced ubiquitinated alpha-synuclein, increased dopamine levels, and improved motor and behavioral symptoms in wild-type (USP13+/+), but not USP13 deficient, mice. These data suggest that USP13 is critical to the neuropathology of alpha-synuclein, whereas a novel small molecule inhibitor of USP13 is a potential therapeutic agent of alpha-synucleinopathies.
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17

Kelly, Rachel, Andrew G. Cairns, Jörgen Ådén, Fredrik Almqvist, Alexis-Pierre Bemelmans, Emmanuel Brouillet, Tommy Patton, Declan P. McKernan, and Eilís Dowd. "The Small Molecule Alpha-Synuclein Aggregator, FN075, Enhances Alpha-Synuclein Pathology in Subclinical AAV Rat Models." Biomolecules 11, no. 11 (November 12, 2021): 1685. http://dx.doi.org/10.3390/biom11111685.

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Animal models of Parkinson’s disease, in which the human α-synuclein transgene is overexpressed in the nigrostriatal pathway using viral vectors, are widely considered to be the most relevant models of the human condition. However, although highly valid, these models have major limitations related to reliability and variability, with many animals exhibiting pronounced α-synuclein expression failing to demonstrate nigrostriatal neurodegeneration or motor dysfunction. Therefore, the aim of this study was to determine if sequential intra-nigral administration of AAV-α-synuclein followed by the small α-synuclein aggregating molecule, FN075, would enhance or precipitate the associated α-synucleinopathy, nigrostriatal pathology and motor dysfunction in subclinical models. Rats were given unilateral intra-nigral injections of AAV-α-synuclein (either wild-type or A53T mutant) followed four weeks later by a unilateral intra-nigral injection of FN075, after which they underwent behavioral testing for lateralized motor functionality until they were sacrificed for immunohistological assessment at 20 weeks after AAV administration. In line with expectations, both of the AAV vectors induced widespread overexpression of human α-synuclein in the substantia nigra and striatum. Sequential administration of FN075 significantly enhanced the α-synuclein pathology with increased density and accumulation of the pathological form of the protein phosphorylated at serine 129 (pS129-α-synuclein). However, despite this enhanced α-synuclein pathology, FN075 did not precipitate nigrostriatal degeneration or motor dysfunction in these subclinical AAV models. In conclusion, FN075 holds significant promise as an approach to enhancing the α-synuclein pathology in viral overexpression models, but further studies are required to determine if alternative administration regimes for this molecule could improve the reliability and variability in these models.
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Barinova, K. V., A. K. Melnikova, E. V. Schmalhausen, and V. I. Muronetz. "A rational approach to obtaining high-specific polyclonal antibodies against recombinant alpha-synuclein." Biomeditsinskaya Khimiya 64, no. 3 (2018): 276–82. http://dx.doi.org/10.18097/pbmc20186403276.

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The approach for the quick and efficient production ofpolyclonal antibodies tothe target antigen alpha-synuclein has been proposed. Two methods have been employed to purify specific rabbit polyclonal antibodies against recombinant human alpha-synuclein, produced by subcutaneous immunization with complete Freund's adjuvant. It was shown that purification on CNBr-activated Sepharose with immobilized alpha-synuclein resulted in antibody preparation with rabbit serum histidine-rich glycoprotein as a contaminant. Two-stage antibody purification procedure first on Sepharose with immobilized protein G, and then on alpha-synuclein immobilized column helps to avoid contamination and to obtain homogenous antibody preparation. Antibodies recognize different conformations of alpha-synuclein and can be used in a variety of immunochemical approaches, including immunocytochemistry.
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19

Liangliang, Xu, Hou Yonghui, E. Shunmei, Gong Shoufang, Zhou Wei, and Zou Jiangying. "Dominant-positive HSF1 decreases alpha-synuclein level and alpha-synuclein-induced toxicity." Molecular Biology Reports 37, no. 4 (July 17, 2009): 1875–81. http://dx.doi.org/10.1007/s11033-009-9623-2.

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20

Liu, Yan, Yu-He Yuan, Jian-Dong Sun, Jing Li, Zhi-Peng Li, and Nai-Hong Chen. "Nigrostriatal dynein changes in A53T alpha-synuclein transgenic mice." F1000Research 3 (March 11, 2014): 68. http://dx.doi.org/10.12688/f1000research.3507.1.

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The accumulation of misfolded a-synuclein is mechanistically linked to neurodegeneration in Parkinson’s disease (PD) and other alpha-synucleinopathies. However, how alpha-synuclein causes neurodegeneration is unresolved. Several studies have supported the involvement of dynein, the major motor for retrograde axonal transport in alpha-synuclein-dependent neurodegeneration, especially in the nigrostriatal system. Therefore, we examined the nigrostriatal dyneins in transgenic mice that overexpress human A53T alpha-synuclein and recapitulate key features of a PD-like neuronal synucleinopathy. Age-matched nontransgenic littermates were used as controls. The results demonstrated that the protein level of dynein was decreased in the striatum, whereas it was elevated in the substantia nigra. Double immunostaining results revealed that the reduction in dynein level was associated with aggregation of A53T a-synuclein in the striatum. Furthermore, we performed a quantitative analysis of motor behaviors in A53T alpha-synuclein transgenic mice and controls using a modified open field test. We demonstrated that the protein level of dynein in the striatum was significantly correlated with the motor behaviors. Together, our data indicate that dynein changes in the nigrostriatal system of A53T alpha-synuclein transgenic mice may contribute to their severe movement disorder.
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21

Assêncio, Franziska Richter. "Alpha-synuclein as therapeutic target in Parkinson’s disease." Neuroforum 25, no. 2 (May 27, 2019): 129–36. http://dx.doi.org/10.1515/nf-2018-0029.

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Zusammenfassung 180 Jahre vergingen zwischen James Parkinson’s “An essay on the shaking palsy” und der Entdeckung der zentralen Rolle von alpha-synuclein in der Pathogenese von Parkinson’s disease (PD). Der Identifikation einer PD verursachenden Mutation im alpha-synuclein Gen folgte rasch der Nachweis des Proteins in Lewy Körperchen, den charakteristischen Proteineinschlüssen im Gehirn der Patienten. Trotz vieler ungeklärter Fragen, Forschungsergebnisse zur Entstehung, Ausbreitung und Neurotoxizität der alpha-synuclein Pathologie geben Hoffnung auf die Entwicklung einer Krankheits-modifizierenden Therapie, über die Dopaminersatztherapie hinaus. Die Hypothese, dass alpha-synuclein Pathologie sich ähnlich wie ein Prion ausbreitet, wird kontrovers diskutiert, und initiierte viele interessante neue Forschungsansätze und therapeutische Zielstrukturen. Dieser Übersichtsartikel fasst die Evidenz für eine zentrale Rolle von alpha-synuclein in der Pathogenese der PD zusammen, gefolgt von einer Diskussion neuer Therapiestrategien.
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Dias, Sarah Batista, Luísa de Lemos, Luís Sousa, Diogo B. Bitoque, Gabriela Araújo Silva, Miguel C. Seabra, and Sandra Tenreiro. "Age-Related Changes of the Synucleins Profile in the Mouse Retina." Biomolecules 13, no. 1 (January 15, 2023): 180. http://dx.doi.org/10.3390/biom13010180.

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Alpha-synuclein (aSyn) plays a central role in Parkinson’s disease (PD) and has been extensively studied in the brain. This protein is part of the synuclein family, which is also composed of beta-synuclein (bSyn) and gamma-synuclein (gSyn). In addition to its neurotoxic role, synucleins have important functions in the nervous system, modulating synaptic transmission. Synucleins are expressed in the retina, but they have been poorly characterized. However, there is evidence that they are important for visual function and that they can play a role in retinal degeneration. This study aimed to profile synucleins in the retina of naturally aged mice and to correlate their patterns with specific retinal cells. With aging, we observed a decrease in the thickness of specific retinal layers, accompanied by an increase in glial reactivity. Moreover, the aSyn levels decreased, whereas bSyn increased with aging. The colocalization of both proteins was decreased in the inner plexiform layer (IPL) of the aged retina. gSyn presented an age-related decrease at the inner nuclear layer but was not significantly changed in the ganglion cell layer. The synaptic marker synaptophysin was shown to be preferentially colocalized with aSyn in the IPL with aging. At the same time, aSyn was found to exist at the presynaptic endings of bipolar cells and was affected by aging. Overall, this study suggests that physiological aging can be responsible for changes in the retinal tissue, implicating functional alterations that could affect synuclein family function.
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Unal-Cevik, Isin, Yasemin Gursoy-Ozdemir, Muge Yemisci, Sevda Lule, Gunfer Gurer, Alp Can, Veronica Müller, Philip J. Kahle, and Turgay Dalkara. "Alpha-Synuclein Aggregation Induced by Brief Ischemia Negatively Impacts Neuronal Survival in vivo: A Study in [A30P]alpha-Synuclein Transgenic Mouse." Journal of Cerebral Blood Flow & Metabolism 31, no. 3 (September 29, 2010): 913–23. http://dx.doi.org/10.1038/jcbfm.2010.170.

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Alpha-synuclein oligomerization and aggregation are considered to have a role in the pathogenesis of neurodegenerative diseases. However, despite numerous in vitro studies, the impact of aggregates in the intact brain is unclear. In vitro, oxidative/nitrative stress and acidity induce α-synuclein oligomerization. These conditions favoring α-synuclein fibrillization are present in the ischemic brain, which may serve as an in vivo model to study α-synuclein aggregation. In this study, we show that 30-minute proximal middle cerebral artery (MCA) occlusion and 72 hours reperfusion induce oligomerization of wild-type α-synuclein in the ischemic mouse brain. The nonamyloidogenic isoform β-synuclein did not form oligomers. Alpha-synuclein aggregates were confined to neurons and colocalized with ubiquitin immunoreactivity. We also found that 30 minutes proximal MCA occlusion and 24 hours reperfusion induced larger infarcts in C57BL/6(Thy1)-h[A30P]alphaSYN transgenic mice, which have an increased tendency to form synuclein fibrils. Trangenics also developed more selective neuronal necrosis when subjected to 20 minutes distal MCA occlusion and 72 hours reperfusion. Enhanced 3-nitrotyrosine immunoreactivity in transgenic mice suggests that oxidative/nitrative stress may be one of the mechanisms mediating aggregate toxicity. Thus, the increased vulnerability of transgenic mice to ischemia suggests that α-synuclein aggregates not only form during ischemia but also negatively impact neuronal survival, supporting the idea that α-synuclein misfolding may be neurotoxic.
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Shameli, Afshin, Yan Zheng, Clifford Harding, Howard Meyerson, and Robert Maitta. "Alpha-Synuclein Deficiency Is Associated with Defective Th2 Differentiation and Enhanced Regulatory T Cell Development." Blood 124, no. 21 (December 6, 2014): 1424. http://dx.doi.org/10.1182/blood.v124.21.1424.1424.

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Abstract Synucleins (including α-, β- and γ-synucleins) are a group of proteins that are highly expressed in the central nervous system. Alpha-synuclein, in particular, has been implicated in the pathogenesis of neurodegenerative disorders known as synucleinopathies. The function of these proteins in other organ systems is largely unknown. Some studies have demonstrated expression of α-synuclein on peripheral blood mononuclear cells (PBMC), including B and T lymphocytes, NK cells and monocytes; and its expression has been shown to be higher in PBMCs of individuals with Parkinson’s compared to healthy controls. We have recently shown that α-synuclein-deficiency is associated with marked defect in development of mature B and T lymphocytes. In particular, we showed enhanced negative selection of developing thymic T cells in the absence α-synuclein. Furthermore, we demonstrated that α-synuclein-deficiency is associated with an impaired IgG response to T cell-dependent antigens. Here we used age and sex-matched α-synuclein knock-out (KO) and wild type (WT) mice to further investigate the lineage differentiation and activation of T cells. We found that few splenic T cells that develop in KO mice contain a higher percentage of CD8+ T cell expressing early activation markers CD69 (7.6 ± 0.09 for KO vs. 5.3 ± 0.23 for WT, p=0.005, figure 1A) and CD49d (12.97 ± 0.3 for KO vs. 7.32 ± 0.6 for WT, p=0.006, figure 1A). A similar trend was noted for CD4+ CD49d+ T cells, although the difference did not reach statistical significance (23.90 ± 3.48 for KO vs.13.23 ± 0.73 for WT, p=0.086, figure 1A). No difference was noted in the expression of late activation marker CD44, and lymph node homing marker CD62L. This was associated with significantly increased IL-2 production from KO CD4+ T cells (OD 2.70 ± 0.12 for KO vs.1.05 ± 0.39 for WT, p=0.002, figure 1B) and a trend for increased IFN-γ production from KO CD4+ T cells (OD 2.89 ± 0.33 for KO vs.2.12 ± 0.59 for WT, p=0.12) after in vitro activation with anti-CD3/anti-CD28 beads. Interestingly, In vitro activation of splenic CD4+ T cells resulted in significantly reduced IL-4 production from KO T cells (OD 0.20 ± 0.14 for KO, vs. 0.74 ± 0.31 for WT, p=0.05, Figure 2) suggesting a defective Th2 differentiation in KO CD4+ T cells. Further flow cytometric analysis of T cells showed that while thymic Foxp3+ CD4+ regulatory T cells are significantly reduced in KO mice (3.07 ±0.35 for KO vs. 5.00 ± 0.87 for WT, p=0.02, Figure 3), the percentage of splenic Foxp3+ CD4+ T cells is higher in the KO mice compared to WT mice (18.33 ± 4.90 for KO vs.10.33 ± 1.39 for WT, p=0.05, Figure 3). No difference was noted among NK cells from KO and WT mice. In summary, we demonstrate a role for α-synuclein in lineage differentiation and function of T cells. While α-synuclein-deficiency leads to a significant defect in development of mature T cells, the small population of cells that do mature, express higher levels of early activation markers, and produce higher levels of IL-2 upon antigenic stimulation. Of interest, these cells are defective in IL-4 production. Additionally, we also show that α-synuclein-deficiency is associated with a higher percentage of peripheral CD4+ Foxp3+ T cells, a finding that might be explained by higher levels of IL-2 production by α-synuclein-deficient CD4+ T cells, although a direct effect of α-synuclein on the survival of regulatory T cells cannot be excluded. The underlying mechanism for the function α-synuclein in development and function of T cells is subject of future studies. Disclosures No relevant conflicts of interest to declare.
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Lee, Seung-Jae, Hyesung Jeon, and Konstantin Kandror. "Alpha-Synuclein is localized in a subpopulation of rat brain synaptic vesicles." Acta Neurobiologiae Experimentalis 68, no. 4 (December 31, 2008): 509–15. http://dx.doi.org/10.55782/ane-2008-1717.

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Alpha-Synuclein is a neuronal protein implicated both in synaptic transmission and in neurodegenerative diseases. Although it is evident that this protein is enriched in the presynaptic terminals of neurons, localization in synaptic vesicles has not been conclusively determined. Here, we show that alpha-synuclein is present, but not enriched, in synaptic vesicles using highly purified synaptic vesicle preparations from rat brain homogenate. Immunoisolation of vesicles using antibodies against synaptophysin or synaptobrevin confirmed the presence of alpha-synuclein in synaptic vesicles. Additional separation of synaptic vesicles by sucrose velocity centrifugation showed that there are different subpopulations of synaptic vesicles and that alpha-synuclein is present only in a specific subpopulation, whereas synaptophysin and synaptobrevin were found in all the synaptic vesicles. Presence of alpha-synuclein only in a subset of synaptic vesicles suggests that this protein may have a specific function in synaptic vesicle cycling, hence in synaptic transmission.
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26

Van Den Berge, Nathalie, Nelson Ferreira, Trine Werenberg Mikkelsen, Aage Kristian Olsen Alstrup, Gültekin Tamgüney, Páll Karlsson, Astrid Juhl Terkelsen, Jens Randel Nyengaard, Poul Henning Jensen, and Per Borghammer. "Ageing promotes pathological alpha-synuclein propagation and autonomic dysfunction in wild-type rats." Brain 144, no. 6 (April 20, 2021): 1853–68. http://dx.doi.org/10.1093/brain/awab061.

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Abstract Neuronal aggregates of misfolded alpha-synuclein protein are found in the brain and periphery of patients with Parkinson’s disease. Braak and colleagues have hypothesized that the initial formation of misfolded alpha-synuclein may start in the gut, and then spread to the brain via peripheral autonomic nerves hereby affecting several organs, including the heart and intestine. Age is considered the greatest risk factor for Parkinson’s disease, but the effect of age on the formation of pathology and its propagation has not been studied in detail. We aimed to investigate whether propagation of alpha-synuclein pathology from the gut to the brain is more efficient in old versus young wild-type rats, upon gastrointestinal injection of aggregated alpha-synuclein. Our results demonstrate a robust age-dependent gut-to-brain and brain-to-gut spread of alpha-synuclein pathology along the sympathetic and parasympathetic nerves, resulting in age-dependent dysfunction of the heart and stomach, as observed in patients with Parkinson’s disease. Moreover, alpha-synuclein pathology is more densely packed and resistant to enzymatic digestion in old rats, indicating an age-dependent maturation of alpha-synuclein aggregates. Our study is the first to provide a detailed investigation of alpha-synuclein pathology in several organs within one animal model, including the brain, skin, heart, intestine, spinal cord and autonomic ganglia. Taken together, our findings suggest that age is a crucial factor for alpha-synuclein aggregation and complete propagation to heart, stomach and skin, similar to patients. Given that age is the greatest risk factor for human Parkinson’s disease, it seems likely that older experimental animals will yield the most relevant and reliable findings. These results have important implications for future research to optimize diagnostics and therapeutics in Parkinson’s disease and other age-associated synucleinopathies. Increased emphasis should be placed on using aged animals in preclinical studies and to elucidate the nature of age-dependent interactions.
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Raghavan, Ravi, Loes de Kruijff, Monique D. Sterrenburg, Beverly B. Rogers, Christa L. Hladik, and Charles L. White. "Alpha-Synuclein Expression in the Developing Human Brain." Pediatric and Developmental Pathology 7, no. 5 (September 2004): 506–16. http://dx.doi.org/10.1007/s10024-003-7080-9.

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Alpha (α)-synuclein is a presynaptic protein, abnormal expression of which has been associated with neurodegenerative and neoplastic diseases. It is abundant in the developing vertebrate central nervous system (CNS), but less is known about its developmental expression in the human CNS. Immunohistochemical expression of α-synuclein was studied in 39 fetal, perinatal, pediatric, and adolescent brains. Perikaryal expression of α-synuclein is observed as early as 11-wk gestation in the cortical plate. Several discrete neuronal groups in the hippocampus, basal ganglia, and brain stem express perikaryal α-synuclein by 20-wk gestation, persisting through the first few years of life. In the cerebellum, α-synuclein is present by 21-wk gestation and persists into adult life as a coarse granular neuropil reaction product in the internal granular layer, and as a diffuse neuropil “blush” in the molecular layer. The germinal matrix, glia, endothelial cells, external granular layer, Pukinje cells, and dentate neurons are consistently negative for α-synuclein. We conclude that α-synuclein is expressed very early in human gestation, and that its distribution and temporal sequence of expression varies in discrete neuronal groups. Perikaryal α-synuclein starts disappearing from the neuronal cytosol in early childhood, and only the neuropil retains immunoreactivity into adulthood. The reappearance of α-synuclein in the adult neuronal cytosol in certain disease processes may represent reemergence of cues from an earlier developmental stage as part of a stress response.
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Miraglia, Fabiana, Verdiana Valvano, Lucia Rota, Cristina Di Primio, Valentina Quercioli, Laura Betti, Gino Giannaccini, Antonino Cattaneo, and Emanuela Colla. "Alpha-Synuclein FRET Biosensors Reveal Early Alpha-Synuclein Aggregation in the Endoplasmic Reticulum." Life 10, no. 8 (August 11, 2020): 147. http://dx.doi.org/10.3390/life10080147.

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Endoplasmic reticulum (ER) dysfunction is important for alpha-synuclein (αS) acquired toxicity. When targeted to the ER in SH-SY5Y cells, transient or stable expression of αS resulted in the formation of compact αS-positive structures in a small subpopulation of cells, resembling αS inclusions. Thus, because of the limitations of immunofluorescence, we developed a set of αS FRET biosensors (AFBs) able to track αS conformation in cells. In native conditions, expression in i36, a stable cell line for ER αS, of intermolecular AFBs, reporters in which CFP or YFP has been fused with the C-terminal of αS (αS-CFP/αS-YFP), resulted in no Förster resonance energy transfer (FRET), whereas expression of the intramolecular AFB, a probe obtained by fusing YFP and CFP with αS N- or C- termini (YFP-αS-CFP), showed a positive FRET signal. These data confirmed that αS has a predominantly globular, monomeric conformation in native conditions. Differently, under pro-aggregating conditions, the intermolecular AFB was able to sense significantly formation of αS oligomers, when AFB was expressed in the ER rather than ubiquitously, suggesting that the ER can favor changes in αS conformation when aggregation is stimulated. These results show the potential of AFBs as a new, valuable tool to track αS conformational changes in vivo.
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Conway, K. A. "Kinetic Stabilization of the alpha -Synuclein Protofibril by a Dopamine-alpha -Synuclein Adduct." Science 294, no. 5545 (November 9, 2001): 1346–49. http://dx.doi.org/10.1126/science.1063522.

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30

Barinova, K. V., M. L. Kuravsky, A. M. Arutyunyan, M. V. Serebryakova, E. V. Schmalhausen, and V. I. Muronetz. "Dimerization of Tyr136Cys alpha-synuclein prevents amyloid transformation of wild type alpha-synuclein." International Journal of Biological Macromolecules 96 (March 2017): 35–43. http://dx.doi.org/10.1016/j.ijbiomac.2016.12.011.

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31

Kapila, Simran, Yuhan Sun, Chao Peng, and Shujing Zhang. "Soluble alpha-synuclein post-translational modifications: unexpected regulators of pathological alpha-synuclein amplification." Neural Regeneration Research 19, no. 5 (September 22, 2023): 959–60. http://dx.doi.org/10.4103/1673-5374.385303.

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32

Glud,2, Andreas, Claus Hedegaard, Mette Nielsen, Jens Sorensen, Christian Bendixen, Poul Jensen, Poul Mogensen, Knud Larsen, and Carsten Bjarkam,2. "Direct MRI-guided stereotaxic viral mediated gene transfer of alpha-synuclein in the Gottingen minipig CNS." Acta Neurobiologiae Experimentalis 71, no. 4 (December 31, 2011): 508–18. http://dx.doi.org/10.55782/ane-2011-1867.

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The aim was to establish a non-primate large animal PD model by lentiviral vector mediated mutant alpha-synuclein overexpression in the substantia nigra. Lentivirus encoding A53T alpha-synuclein (6 x 2.5 microliter) was stereotaxically injected into the substantia nigra of six adult female Gottingen minipigs. Contralateral control injections encoding enhanced green fluorescent protein (EGFP) were performed. Gait-analysis was performed pre- and postoperatively. PCR of the transgenes and immunohistochemical staining against alpha-synuclein, EGFP, GFAP and TH was performed after 20 weeks. Gait analysis revealed a significant increase in step length and height, and a decrease in the double stand phase. PCR verified the mesencephalic presence of transgenes. IHC analysis showed alpha-synuclein expression in nigral neurons, around the injection tract and in related nigrostriatal projections. The alpha-synuclein positive neurons appeared swollen and vacuolated, in contrast to the EGFP-injected control side. To transduct all nigrostriatal cells with few microinjections, wider dissemination of the transgene must be achieved.
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33

Shen, Ning, Ge Song, Haiqiang Yang, Xiaoyang Lin, Breanna Brown, Yuzhu Hong, Jianfeng Cai, and Chuanhai Cao. "Identifying the Pathological Domain of Alpha- Synuclein as a Therapeutic for Parkinson’s Disease." International Journal of Molecular Sciences 20, no. 9 (May 11, 2019): 2338. http://dx.doi.org/10.3390/ijms20092338.

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Alpha-synuclein is considered the major pathological protein associated with Parkinson’s disease, but there is still no effective immunotherapy which targets alpha-synuclein. In order to create a safer and more effective therapy against PD, we are targeting an epitope of alpha-synuclein rather than full-length alpha-synuclein. We have selected several antigenic domains (B-cell epitope) through antigenicity prediction, and also made several recombinant protein fragments from alpha-synuclein upon antigenicity prediction in an E. coli system. We then tested the function of each of the peptides and recombinant fragments in aggregation, their toxicity and antigenicity. We have discovered that the full-length recombinant (aa1–140) can aggregate into oligomers or even fibrils, and fragment aa15–65 can promote the aggregation of aa1–140. It is worth noting that it not only promotes whole protein aggregation, but also self-aggregates as seen by western blotting and silver staining assays. We have tested all candidates on primary neurons for their toxicity and discovered that aa15–65 is the most toxic domain compared to all other fragments. The antibody targeting this domain also showed both anti-aggregation activity and some therapeutic effect. Therefore, we believe that we have identified the most potent therapeutic domain of alpha synuclein as a therapeutic target.
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Arotcarena, Marie-Laure, Margaux Teil, and Benjamin Dehay. "Autophagy in Synucleinopathy: The Overwhelmed and Defective Machinery." Cells 8, no. 6 (June 9, 2019): 565. http://dx.doi.org/10.3390/cells8060565.

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Alpha-synuclein positive-intracytoplasmic inclusions are the common denominators of the synucleinopathies present as Lewy bodies in Parkinson’s disease, dementia with Lewy bodies, or glial cytoplasmic inclusions in multiple system atrophy. These neurodegenerative diseases also exhibit cellular dyshomeostasis, such as autophagy impairment. Several decades of research have questioned the potential link between the autophagy machinery and alpha-synuclein protein toxicity in synucleinopathy and neurodegenerative processes. Here, we aimed to discuss the active participation of autophagy impairment in alpha-synuclein accumulation and propagation, as well as alpha-synuclein-independent neurodegenerative processes in the field of synucleinopathy. Therapeutic approaches targeting the restoration of autophagy have started to emerge as relevant strategies to reverse pathological features in synucleinopathies.
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35

Kondratyev, Maxim S., Vladimir R. Rudnev, Kirill S. Nikolsky, Denis V. Petrovsky, Liudmila I. Kulikova, Kristina A. Malsagova, Alexander A. Stepanov, Arthur T. Kopylov, and Anna L. Kaysheva. "In Silico Study of the Interactions of Anle138b Isomer, an Inhibitor of Amyloid Aggregation, with Partner Proteins." International Journal of Molecular Sciences 23, no. 24 (December 17, 2022): 16096. http://dx.doi.org/10.3390/ijms232416096.

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Herein, we aimed to highlight current “gaps” in the understanding of the potential interactions between the Anle138b isomer ligand, a promising agent for clinical research, and the intrinsically disordered alpha-synuclein protein. The presence of extensive unstructured areas in alpha-synuclein determines its existence in the cell of partner proteins, including the cyclophilin A chaperone, which prevents the aggregation of alpha-synuclein molecules that are destructive to cell life. Using flexible and cascaded molecular docking techniques, we aimed to expand our understanding of the molecular architecture of the protein complex between alpha-synuclein, cyclophilin A and the Anle138b isomer ligand. We demonstrated the possibility of intricate complex formation under cellular conditions and revealed that the main interactions that stabilize the complex are hydrophobic and involve hydrogen.
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36

Кулабухова, Д. Г., А. К. Емельянов, К. А. Сенкевич, Е. В. Грачева, И. В. Милюхина, Н. А. Верлов, Е. Ю. Варфоломеева, А. А. Тимофеева, А. Л. Шварцман, and С. Н. Пчелина. "Plasma exosomal alpha-synuclein in inherited forms of Parkinson’s disease." Nauchno-prakticheskii zhurnal «Medicinskaia genetika», no. 4(213) (April 30, 2020): 99–100. http://dx.doi.org/10.25557/2073-7998.2020.04.99-100.

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Предполагается, что экзосомы (микровезикулы размером 40-100 нм) могут играть ключевую роль в транспорте патогенных форм альфа-синуклеина при болезни Паркинсона (БП). В настоящем исследовании проведена оценка влияния мутаций в генах GBA и LRRK2 на уровень альфа-синуклеина экзосом плазмы крови. Показано, что мутации в генах GBA и LRRK2 не влияют на уровень альфа-синуклеина экзосом плазмы крови. Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder. Alpha-synuclein misfolding and aggregation resulting in neurototoxicity is a hallmark of PD. Exosomes (extrcellular vesicles 40-100 nm in size) can play a key role in the transport of pathogenic forms of alpha-synuclein. The aim of our work is to evaluate an effect of GBA and LRRK2 mutations on alpha-synuclein level in exosomes derived from peripheral blood plasma. No significant difference was found for exosomal alpha-synuclein levels patients with sporadic, GBA- and LRRK2- associated PD, PD with dementia compared to controls. Our results indicate that mutations in the LRRK2 and GBA genes do not influence on plasma exosomal alpha-synuclein level.
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Valdinocci, Dario, Rowan Radford, Michael Goulding, Junna Hayashi, Roger Chung, and Dean Pountney. "Extracellular Interactions of Alpha-Synuclein in Multiple System Atrophy." International Journal of Molecular Sciences 19, no. 12 (December 19, 2018): 4129. http://dx.doi.org/10.3390/ijms19124129.

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Multiple system atrophy, characterized by atypical Parkinsonism, results from central nervous system (CNS) cell loss and dysfunction linked to aggregates of the normally pre-synaptic α-synuclein protein. Mostly cytoplasmic pathological α-synuclein inclusion bodies occur predominantly in oligodendrocytes in affected brain regions and there is evidence that α-synuclein released by neurons is taken up preferentially by oligodendrocytes. However, extracellular α-synuclein has also been shown to interact with other neural cell types, including astrocytes and microglia, as well as extracellular factors, mediating neuroinflammation, cell-to-cell spread and other aspects of pathogenesis. Here, we review the current evidence for how α-synuclein present in the extracellular milieu may act at the cell surface to drive components of disease progression. A more detailed understanding of the important extracellular interactions of α-synuclein with neuronal and non-neuronal cell types both in the brain and periphery may provide new therapeutic targets to modulate the disease process.
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38

Hoffmann, Christian, Roberto Sansevrino, Giuseppe Morabito, Chinyere Logan, R. Martin Vabulas, Ayse Ulusoy, Marcelo Ganzella, and Dragomir Milovanovic. "Synapsin Condensates Recruit alpha-Synuclein." Journal of Molecular Biology 433, no. 12 (June 2021): 166961. http://dx.doi.org/10.1016/j.jmb.2021.166961.

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39

Barbut, Denise, Ethan Stolzenberg, and Michael Zasloff. "Gastrointestinal Immunity and Alpha-Synuclein." Journal of Parkinson's Disease 9, s2 (October 30, 2019): S313—S322. http://dx.doi.org/10.3233/jpd-191702.

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40

Gallastegui, Edurne, Carla Domuro, Joan Serratosa, Alejandra Larrieux, Laura Sin, Jonatan Martinez, Arnaud Besson, et al. "p27Kip1 regulates alpha-synuclein expression." Oncotarget 9, no. 23 (March 27, 2018): 16368–79. http://dx.doi.org/10.18632/oncotarget.24687.

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41

Goedert, Michel. "Alpha-synuclein and neurodegenerative diseases." Nature Reviews Neuroscience 2, no. 7 (July 2001): 492–501. http://dx.doi.org/10.1038/35081564.

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42

LIU, H. "Alpha-synuclein and Parkinson disease." Neural Regeneration Research 2, no. 4 (April 2007): 239–43. http://dx.doi.org/10.1016/s1673-5374(07)60053-x.

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43

Lücking, C. B., and A. Brice*. "Alpha-synuclein and Parkinson's disease." Cellular and Molecular Life Sciences 57, no. 13 (December 2000): 1894–908. http://dx.doi.org/10.1007/pl00000671.

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44

Butler, Brittany, Danielle Sambo, and Habibeh Khoshbouei. "Alpha-synuclein modulates dopamine neurotransmission." Journal of Chemical Neuroanatomy 83-84 (October 2017): 41–49. http://dx.doi.org/10.1016/j.jchemneu.2016.06.001.

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45

Ritchie, Caroline M., and Philip J. Thomas. "Alpha-synuclein truncation and disease." Health 04, no. 11 (2012): 1167–77. http://dx.doi.org/10.4236/health.2012.431175.

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46

Schwarzman, A. L., K. A. Senkevich, A. K. Emelyanov, and S. N. Pchelina. "Prion Properties of Alpha-Synuclein." Molecular Biology 53, no. 3 (May 2019): 335–41. http://dx.doi.org/10.1134/s002689331903018x.

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47

Richter, Franziska. "Lighting Up Alpha-synuclein Oligomers." EBioMedicine 29 (March 2018): 3–4. http://dx.doi.org/10.1016/j.ebiom.2018.02.016.

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48

Forloni, Gianluigi. "Alpha Synuclein: Neurodegeneration and Inflammation." International Journal of Molecular Sciences 24, no. 6 (March 21, 2023): 5914. http://dx.doi.org/10.3390/ijms24065914.

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Alpha-Synuclein (α-Syn) is one of the most important molecules involved in the pathogenesis of Parkinson’s disease and related disorders, synucleinopathies, but also in several other neurodegenerative disorders with a more elusive role. This review analyzes the activities of α-Syn, in different conformational states, monomeric, oligomeric and fibrils, in relation to neuronal dysfunction. The neuronal damage induced by α-Syn in various conformers will be analyzed in relation to its capacity to spread the intracellular aggregation seeds with a prion-like mechanism. In view of the prominent role of inflammation in virtually all neurodegenerative disorders, the activity of α-Syn will also be illustrated considering its influence on glial reactivity. We and others have described the interaction between general inflammation and cerebral dysfunctional activity of α-Syn. Differences in microglia and astrocyte activation have also been observed when in vivo the presence of α-Syn oligomers has been combined with a lasting peripheral inflammatory effect. The reactivity of microglia was amplified, while astrocytes were damaged by the double stimulus, opening new perspectives for the control of inflammation in synucleinopathies. Starting from our studies in experimental models, we extended the perspective to find useful pointers to orient future research and potential therapeutic strategies in neurodegenerative disorders.
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Golbe, Lawrence I. "Alpha-synuclein and Parkinson's disease." Movement Disorders 14, no. 1 (January 1999): 6–9. http://dx.doi.org/10.1002/1531-8257(199901)14:1<6::aid-mds1004>3.0.co;2-l.

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50

Teive, Hélio A. G., Salmo Raskin, Fábio M. Iwamoto, Francisco M. B. Germiniani, Maria H. H. Baran, Lineu C. Werneck, Nasser Allan, et al. "The G209A mutation in the alpha-synuclein gene in Brazilian families with Parkinson's disease." Arquivos de Neuro-Psiquiatria 59, no. 3B (September 2001): 722–24. http://dx.doi.org/10.1590/s0004-282x2001000500013.

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A missense G209A mutation of the alpha-synuclein gene was recently described in a large Contursi kindred with Parkinson's disease (PD). The objective of this study is to determine if the mutation G209A of the alpha-synuclein gene was present in 10 Brazilian families with PD. PD patients were recruited from movement disorders clinics of Brazil. A family history with two or more affected in relatives was the inclusion criterion for this study. The alpha-synuclein G209A mutation assay was made using polymerase chain reaction and the restriction enzyme Tsp45I. Ten patients from 10 unrelated families were studied. The mean age of PD onset was 42.7 years old. We did not find the G209A mutation in our 10 families with PD. Our results suggest that alpha-synuclein mutation G209A is uncommon in Brazilian PD families.
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