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Journal articles on the topic 'Complexe C9ORF72'

Author: Grafiati

Published: 7 July 2024

Last updated: 31 July 2025

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1

Tang, Dan, Jingwen Sheng, Liangting Xu, et al. "Cryo-EM structure of C9ORF72–SMCR8–WDR41 reveals the role as a GAP for Rab8a and Rab11a." Proceedings of the National Academy of Sciences 117, no. 18 (2020): 9876–83. http://dx.doi.org/10.1073/pnas.2002110117.

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A massive intronic hexanucleotide repeat (GGGGCC) expansion in C9ORF72 is a genetic origin of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recently, C9ORF72, together with SMCR8 and WDR41, has been shown to regulate autophagy and function as Rab GEF. However, the precise function of C9ORF72 remains unclear. Here, we report the cryogenic electron microscopy (cryo-EM) structure of the human C9ORF72–SMCR8–WDR41 complex at a resolution of 3.2 Å. The structure reveals the dimeric assembly of a heterotrimer of C9ORF72–SMCR8–WDR41. Notably, the C-terminal tail of C9ORF72 and

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2

Alvarez-Mora, Maria Isabel, Gloria Garrabou, Tamara Barcos, et al. "Bioenergetic and Autophagic Characterization of Skin Fibroblasts from C9orf72 Patients." Antioxidants 11, no. 6 (2022): 1129. http://dx.doi.org/10.3390/antiox11061129.

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The objective of this study is to describe the alterations occurring during the neurodegenerative process in skin fibroblast cultures from C9orf72 patients. We characterized the oxidative stress, autophagy flux, small ubiquitin-related protein SUMO2/3 levels as well as the mitochondrial function in skin fibroblast cultures from C9orf72 patients. All metabolic and bioenergetic findings were further correlated with gene expression data obtained from RNA sequencing analysis. Fibroblasts from C9orf72 patients showed a 30% reduced expression of C9orf72, ~3-fold increased levels of oxidative stress

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3

Nörpel, Julia, Simone Cavadini, Andreas D. Schenk, et al. "Structure of the human C9orf72-SMCR8 complex reveals a multivalent protein interaction architecture." PLOS Biology 19, no. 7 (2021): e3001344. http://dx.doi.org/10.1371/journal.pbio.3001344.

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A major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum disorder is the hexanucleotide G4C2 repeat expansion in the first intron of the C9orf72 gene. Many underlying mechanisms lead to manifestation of disease that include toxic gain-of-function by repeat G4C2 RNAs, dipeptide repeat proteins, and a reduction of the C9orf72 gene product. The C9orf72 protein interacts with SMCR8 and WDR41 to form a trimeric complex and regulates multiple cellular pathways including autophagy. Here, we report the structure of the C9orf72-SMCR8 complex at 3.8 Å reso

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4

Amick, Joseph, Arun Kumar Tharkeshwar, Catherine Amaya,, and Shawn M. Ferguson. "WDR41 supports lysosomal response to changes in amino acid availability." Molecular Biology of the Cell 29, no. 18 (2018): 2213–27. http://dx.doi.org/10.1091/mbc.e17-12-0703.

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C9orf72 mutations are a major cause of amyotrophic lateral sclerosis and frontotemporal dementia. The C9orf72 protein undergoes regulated recruitment to lysosomes and has been broadly implicated in control of lysosome homeostasis. However, although evidence strongly supports an important function for C9orf72 at lysosomes, little is known about the lysosome recruitment mechanism. In this study, we identify an essential role for WDR41, a prominent C9orf72 interacting protein, in C9orf72 lysosome recruitment. Analysis of human WDR41 knockout cells revealed that WDR41 is required for localization

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5

Yang, Mei, Chen Liang, Kunchithapadam Swaminathan, et al. "A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy." Science Advances 2, no. 9 (2016): e1601167. http://dx.doi.org/10.1126/sciadv.1601167.

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The intronic GGGGCC hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) is a prevalent genetic abnormality identified in both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Smith-Magenis syndrome chromosomal region candidate gene 8 (SMCR8) is a protein with unclear functions. We report that C9ORF72 is a component of a multiprotein complex containing SMCR8, WDR41, and ATG101 (an important regulator of autophagy). The C9ORF72 complex displays guanosine triphosphatase (GTPase) activity and acts as a guanosine diphosphate–guanosine 5′-triphosphat

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6

Amick, Joseph, Agnes Roczniak-Ferguson, and Shawn M. Ferguson. "C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling." Molecular Biology of the Cell 27, no. 20 (2016): 3040–51. http://dx.doi.org/10.1091/mbc.e16-01-0003.

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Hexanucleotide expansion in an intron of the C9orf72 gene causes amyotrophic lateral sclerosis and frontotemporal dementia. However, beyond bioinformatics predictions that suggested structural similarity to folliculin, the Birt-Hogg-Dubé syndrome tumor suppressor, little is known about the normal functions of the C9orf72 protein. To address this problem, we used genome-editing strategies to investigate C9orf72 interactions, subcellular localization, and knockout (KO) phenotypes. We found that C9orf72 robustly interacts with SMCR8 (a protein of previously unknown function). We also observed tha

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7

Iyer, Shalini, Vasanta Subramanian, and K. Ravi Acharya. "C9orf72, a protein associated with amyotrophic lateral sclerosis (ALS) is a guanine nucleotide exchange factor." PeerJ 6 (October 17, 2018): e5815. http://dx.doi.org/10.7717/peerj.5815.

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two late onset neurodegenerative diseases, have been shown to share overlapping cellular pathologies and genetic origins. Studies suggest that a hexanucleotide repeat expansion in the first intron of the C9orf72 gene is the most common cause of familial FTD and ALS pathology. The C9orf72 protein is predicted to be a differentially expressed in normal and neoplastic cells domain protein implying that C9orf72 functions as a guanine nucleotide exchange factor (GEF) to regulate specific Rab GTPases. Reported studies thus far po

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8

Chong, Zhao Zhong, and Nizar Souayah. "Targeting Gene C9orf72 Pathogenesis for Amyotrophic Lateral Sclerosis." International Journal of Molecular Sciences 26, no. 9 (2025): 4276. https://doi.org/10.3390/ijms26094276.

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Amyotrophic lateral sclerosis (ALS) is a fatal adult neurodegenerative disorder. Since no cure has been found, finding effective therapeutic targets for ALS remains a major challenge. Gene C9orf72 mutations with the formation of hexanucleotide repeat (GGGGCC) expansion (HRE) have been considered the most common genetic pathogenesis of ALS. The literature review indicates that the C9orf72 HRE causes both the gain-of-function toxicity and loss of function of C9ORF72. The formation of RNA foci and dipeptide repeats (DPRs) resulting from HRE is responsible for toxic function gain. The RNA foci can

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9

Chandra, Sunandini, and C. Patrick Lusk. "Emerging Connections between Nuclear Pore Complex Homeostasis and ALS." International Journal of Molecular Sciences 23, no. 3 (2022): 1329. http://dx.doi.org/10.3390/ijms23031329.

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Developing effective treatments for neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) requires understanding of the underlying pathomechanisms that contribute to the motor neuron loss that defines the disease. As it causes the largest fraction of familial ALS cases, considerable effort has focused on hexanucleotide repeat expansions in the C9ORF72 gene, which encode toxic repeat RNA and dipeptide repeat (DPR) proteins. Both the repeat RNA and DPRs interact with and perturb multiple elements of the nuclear transport machinery, including shuttling nuclear transport receptors

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10

Ababneh, Nidaa A., Jakub Scaber, Rowan Flynn, et al. "Correction of amyotrophic lateral sclerosis related phenotypes in induced pluripotent stem cell-derived motor neurons carrying a hexanucleotide expansion mutation in C9orf72 by CRISPR/Cas9 genome editing using homology-directed repair." Human Molecular Genetics 29, no. 13 (2020): 2200–2217. http://dx.doi.org/10.1093/hmg/ddaa106.

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Abstract The G4C2 hexanucleotide repeat expansion (HRE) in C9orf72 is the commonest cause of familial amyotrophic lateral sclerosis (ALS). A number of different methods have been used to generate isogenic control lines using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and non-homologous end-joining by deleting the repeat region, with the risk of creating indels and genomic instability. In this study, we demonstrate complete correction of an induced pluripotent stem cell (iPSC) line derived from a C9orf72-HRE positive ALS/frontotemporal dementia patient using CRISPR/

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11

Liang, Chen, Qiang Shao, Wei Zhang, et al. "Smcr8 deficiency disrupts axonal transport-dependent lysosomal function and promotes axonal swellings and gain of toxicity in C9ALS/FTD mouse models." Human Molecular Genetics 28, no. 23 (2019): 3940–53. http://dx.doi.org/10.1093/hmg/ddz230.

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Abstract G4C2 repeat expansions in an intron of C9ORF72 cause the most common familial amyotrophic lateral sclerosis and frontotemporal dementia (collectively, C9ALS/FTD). Mechanisms and mediators of C9ALS/FTD pathogenesis remain poorly understood. C9orf72 and Smcr8 form a protein complex. Here, we show that expression of Smcr8, like C9orf72, is reduced in C9ALS/FTD mouse models and patient tissues. Since Smcr8 is highly conserved between human and mouse, we evaluated the effects of Smcr8 downregulation in mice. Smcr8 knockout (KO) mice exhibited motor behavior deficits, which resemble those o

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12

Vidhyasagar, Venkatasubramanian, Yujiong He, Manhong Guo, et al. "Biochemical characterization of INTS3 and C9ORF80, two subunits of hNABP1/2 heterotrimeric complex in nucleic acid binding." Biochemical Journal 475, no. 1 (2018): 45–60. http://dx.doi.org/10.1042/bcj20170351.

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Human nucleic acid-binding protein 1 and 2 (hNABP1 and hNABP2, also known as hSSB2 and hSSB1 respectively) form two separate and independent complexes with two identical proteins, integrator complex subunit 3 (INTS3) and C9ORF80. We and other groups have demonstrated that hNABP1 and 2 are single-stranded (ss) DNA- and RNA-binding proteins, and function in DNA repair; however, the function of INTS3 and C9OFR80 remains elusive. In the present study, we purified recombinant proteins INTS3 and C9ORF80 to near homogeneity. Both proteins exist as a monomer in solution; however, C9ORF80 exhibits anom

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13

McAlpine, William, Lei Sun, Kuan-wen Wang, et al. "Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function." Proceedings of the National Academy of Sciences 115, no. 49 (2018): E11523—E11531. http://dx.doi.org/10.1073/pnas.1814753115.

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The SMCR8-WDR41-C9ORF72 complex is a regulator of autophagy and lysosomal function. Autoimmunity and inflammatory disease have been ascribed to loss-of-function mutations of Smcr8 or C9orf72 in mice. In humans, autoimmunity has been reported to precede amyotrophic lateral sclerosis caused by mutations of C9ORF72. However, the cellular and molecular mechanisms underlying autoimmunity and inflammation caused by C9ORF72 or SMCR8 deficiencies remain unknown. Here, we show that splenomegaly, lymphadenopathy, and activated circulating T cells observed in Smcr8−/− mice were rescued by triple knockout

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14

Talaia, Gabriel, Joseph Amick, and Shawn M. Ferguson. "Receptor-like role for PQLC2 amino acid transporter in the lysosomal sensing of cationic amino acids." Proceedings of the National Academy of Sciences 118, no. 8 (2021): e2014941118. http://dx.doi.org/10.1073/pnas.2014941118.

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PQLC2, a lysosomal cationic amino acid transporter, also serves as a sensor that responds to scarcity of its substrates by recruiting a protein complex composed of C9orf72, SMCR8, and WDR41 to the surface of lysosomes. This protein complex controls multiple aspects of lysosome function. Although it is known that this response to changes in cationic amino acid availability depends on an interaction between PQLC2 and WDR41, the underlying mechanism for the regulated interaction is not known. In this study, we present evidence that the WDR41–PQLC2 interaction is mediated by a short peptide motif

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15

Fumagalli, Laura, Florence L. Young, Steven Boeynaems, et al. "C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility." Science Advances 7, no. 15 (2021): eabg3013. http://dx.doi.org/10.1126/sciadv.abg3013.

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A hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this mutation leads to these neurodegenerative diseases remains unclear. Here, we show using patient stem cell–derived motor neurons that the repeat expansion impairs microtubule-based transport, a process critical for neuronal survival. Cargo transport defects are recapitulated by treating neurons from healthy individuals with proline-arginine and glycine-arginine dipeptide repeats (DPRs) produced from the repeat expansion. Both a

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16

Fukatsu, Shoya, Hinami Sashi, Remina Shirai, et al. "Rab11a Controls Cell Shape via C9orf72 Protein: Possible Relationships to Frontotemporal Dementia/Amyotrophic Lateral Sclerosis (FTDALS) Type 1." Pathophysiology 31, no. 1 (2024): 100–116. http://dx.doi.org/10.3390/pathophysiology31010008.

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Abnormal nucleotide insertions of C9orf72, which forms a complex with Smith–Magenis syndrome chromosomal region candidate gene 8 (SMCR8) protein and WD repeat-containing protein 41 (WDR41) protein, are associated with an autosomal-dominant neurodegenerative frontotemporal dementia and/or amyotrophic lateral sclerosis type 1 (FTDALS1). The differentially expressed in normal and neoplastic cells (DENN) domain-containing C9orf72 and its complex with SMCR8 and WDR41 function as a guanine-nucleotide exchange factor for Rab GTP/GDP-binding proteins (Rab GEF, also called Rab activator). Among Rab pro

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17

Cook, Casey N., Yanwei Wu, Hana M. Odeh, et al. "C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy." Science Translational Medicine 12, no. 559 (2020): eabb3774. http://dx.doi.org/10.1126/scitranslmed.abb3774.

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TAR DNA-binding protein 43 (TDP-43) inclusions are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), including cases caused by G4C2 repeat expansions in the C9orf72 gene (c9FTD/ALS). Providing mechanistic insight into the link between C9orf72 mutations and TDP-43 pathology, we demonstrated that a glycine-arginine repeat protein [poly(GR)] translated from expanded G4C2 repeats was sufficient to promote aggregation of endogenous TDP-43. In particular, toxic poly(GR) proteins mediated sequestration of full-length TDP-43 in an RNA-independent manner

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18

Coyne, Alyssa N., Victoria Baskerville, Benjamin L. Zaepfel, et al. "Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS." Science Translational Medicine 13, no. 604 (2021): eabe1923. http://dx.doi.org/10.1126/scitranslmed.abe1923.

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Alterations in the components [nucleoporins (Nups)] and function of the nuclear pore complex (NPC) have been implicated as contributors to the pathogenesis of genetic forms of neurodegeneration including C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). We hypothesized that Nup alterations and the consequential loss of NPC function may lie upstream of TDP-43 dysfunction and mislocalization widely observed in ALS, FTD, and related neurodegenerative diseases. Here, we provide evidence that CHMP7, a critical mediator of NPC quality control, is increased in nuclei of C9orf72

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19

Costa, Beatrice, Claudia Manzoni, Manuel Bernal-Quiros, et al. "C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts." Neurology 95, no. 24 (2020): e3288-e3302. http://dx.doi.org/10.1212/wnl.0000000000010914.

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ObjectiveWe sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.MethodsWe evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD–motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion s

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20

Lee, Jongbo, Jumin Park, Ji-hyung Kim, et al. "LSM12-EPAC1 defines a neuroprotective pathway that sustains the nucleocytoplasmic RAN gradient." PLOS Biology 18, no. 12 (2020): e3001002. http://dx.doi.org/10.1371/journal.pbio.3001002.

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Nucleocytoplasmic transport (NCT) defects have been implicated in neurodegenerative diseases such as C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Here, we identify a neuroprotective pathway of like-Sm protein 12 (LSM12) and exchange protein directly activated by cyclic AMP 1 (EPAC1) that sustains the nucleocytoplasmic RAN gradient and thereby suppresses NCT dysfunction by the C9ORF72-derived poly(glycine-arginine) protein. LSM12 depletion in human neuroblastoma cells aggravated poly(GR)-induced impairment of NCT and nuclear integrity while promotin

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21

Pilotto, Andrea, Mattia Carini, Roberto Bresciani, et al. "Next Generation Sequencing Analysis in Patients Affected by Parkinson’s Disease and Correlation Between Genotype and Phenotype in Selected Clinical Cases." International Journal of Molecular Sciences 26, no. 6 (2025): 2397. https://doi.org/10.3390/ijms26062397.

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Parkinson’s Disease (PD) is the most frequent movement disorder and is second only to Alzheimer’s Disease as the most frequent neurodegenerative pathology. Early onset Parkinson’s disease (EOPD) is less common and may be characterized by genetic predisposition. NGS testing might be useful in the diagnostic assessment of these patients. A panel of eight genes (SNCA, PRKN, PINK1, DJ1, LRRK2, FBXO7, GBA1 and HFE) was validated and used as a diagnostic tool. A total of 38 in sequence EOPD patients of the Parkinson’s Disease Unit of our Hospital Institution were tested. In addition, the number of t

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22

Kaur, Jaslovleen, Shaista Parveen, Uzma Shamim, et al. "Investigations of Huntington’s Disease and Huntington’s Disease-Like Syndromes in Indian Choreatic Patients." Journal of Huntington's Disease 9, no. 3 (2020): 283–89. http://dx.doi.org/10.3233/jhd-200398.

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Background: The diagnostic workup for choreiform movement disorders including Huntington’s disease (HD) and those mimicking HD like phenotype is complex. Objective: The aim of the present study was to genetically define HD and HD-like presentations in an Indian cohort. We also describe HTT-CAG expansion manifesting as neuroferritinopathy-like disorder in four families from Punjab in India. Materials and methods: 159 patients clinically diagnosed as HD and HD-like presentations from various tertiary neurology clinics were referred to our centre (CSIR-IGIB) for genetic investigations. As a first

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González-Sánchez, María, María Jesús Ramírez-Expósito, and José Manuel Martínez-Martos. "Pathophysiology, Clinical Heterogeneity, and Therapeutic Advances in Amyotrophic Lateral Sclerosis: A Comprehensive Review of Molecular Mechanisms, Diagnostic Challenges, and Multidisciplinary Management Strategies." Life 15, no. 4 (2025): 647. https://doi.org/10.3390/life15040647.

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons, leading to muscle atrophy, paralysis, and respiratory failure. This comprehensive review synthesizes the current knowledge on ALS pathophysiology, clinical heterogeneity, diagnostic frameworks, and evolving therapeutic strategies. Mechanistically, ALS arises from complex interactions between genetic mutations (e.g., in C9orf72, SOD1, TARDBP (TDP-43), and FUS) and dysregulated cellular pathways, including impaired RNA metabolism, protein

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Takada, Leonel T. "The Genetics of Monogenic Frontotemporal Dementia." Dementia & Neuropsychologia 9, no. 3 (2015): 219–29. http://dx.doi.org/10.1590/1980-57642015dn93000003.

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ABSTRACT Around 10-15% of patients diagnosed with frontotemporal dementia (FTD) have a positive family history for FTD with an autosomal dominant pattern of inheritance. Since the identification of mutations in MAPT(microtubuleassociated protein tau gene) in 1998, over 10 other genes have been associated with FTD spectrum disorders, discussed in this review. Along with MAPT, mutations in GRN(progranulin) and C9orf72(chromosome 9 open reading frame 72) are the most commonly identified in FTD cohorts. The association of FTD and motor neuron disease (MND) can be caused by mutations in C9orf72and

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Magrath-Guimet, Nahuel. "Frontotemporal dementia: past, present and future." Journal of Applied Cognitive Neuroscience 5, no. 1 (2024): e5566. http://dx.doi.org/10.17981/jacn.5.1.2024.06.

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This scientific review comprehensively addresses frontotemporal dementia (FTD), providing a comprehensive overview of its historical evolution, clinical typology, underlying pathology, genetic basis and therapeutic approaches. The clinical diversity ofFTD and the importance of understanding its distinctive symptomatic manifestations are highlighted. The review explores the pathology, highlighting the accumulation of proteins such as tau and TDP-43, and explores the genetic implications, with emphasis on key mutations such as MAPT, progranulin and c9orf72. In addition to reviewing pharmacologic

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Shi, Kevin Y., Eiichiro Mori, Zehra F. Nizami, et al. "Toxic PRn poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export." Proceedings of the National Academy of Sciences 114, no. 7 (2017): E1111—E1117. http://dx.doi.org/10.1073/pnas.1620293114.

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The toxic proline:arginine (PRn) poly-dipeptide encoded by the (GGGGCC)n repeat expansion in the C9orf72 form of heritable amyotrophic lateral sclerosis (ALS) binds to the central channel of the nuclear pore and inhibits the movement of macromolecules into and out of the nucleus. The PRn poly-dipeptide binds to polymeric forms of the phenylalanine:glycine (FG) repeat domain, which is shared by several proteins of the nuclear pore complex, including those in the central channel. A method of chemical footprinting was used to characterize labile, cross-β polymers formed from the FG domain of the

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Wong, Ching-On, and Kartik Venkatachalam. "Motor neurons from ALS patients with mutations in C9ORF72 and SOD1 exhibit distinct transcriptional landscapes." Human Molecular Genetics 28, no. 16 (2019): 2799–810. http://dx.doi.org/10.1093/hmg/ddz104.

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Abstract Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that culminates in paralysis and death. Here, we present our analyses of publicly available multiOMIC data sets generated using motor neurons from ALS patients and control cohorts. Functional annotation of differentially expressed genes in induced pluripotent stem cell (iPSC)-derived motor neurons generated from patients with mutations in C9ORF72 (C9-ALS) suggests elevated expression of genes that pertain to extracellular matrix (ECM) and cell adhesion, inflammation and TGFβ targets. On the other end of the cont

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Morello, Giovanna, Giulia Gentile, Rossella Spataro, et al. "Genomic Portrait of a Sporadic Amyotrophic Lateral Sclerosis Case in a Large Spinocerebellar Ataxia Type 1 Family." Journal of Personalized Medicine 10, no. 4 (2020): 262. http://dx.doi.org/10.3390/jpm10040262.

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Background: Repeat expansions in the spinocerebellar ataxia type 1 (SCA1) gene ATXN1 increases the risk for amyotrophic lateral sclerosis (ALS), supporting a relationship between these disorders. We recently reported the co-existence, in a large SCA1 family, of a clinically definite ALS individual bearing an intermediate ATXN1 expansion and SCA1 patients with a full expansion, some of which manifested signs of lower motor neuron involvement. Methods: In this study, we employed a systems biology approach that integrated multiple genomic analyses of the ALS patient and some SCA1 family members.

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de Boer, Eva Maria Johanna, Viyanti K. Orie, Timothy Williams, et al. "TDP-43 proteinopathies: a new wave of neurodegenerative diseases." Journal of Neurology, Neurosurgery & Psychiatry 92, no. 1 (2020): 86–95. http://dx.doi.org/10.1136/jnnp-2020-322983.

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Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases. For instance, the majority of patients with sporadic amyotrophic lateral sclerosis (up to 97%) and a substantial proportion of patients with frontotemporal lobar degeneration (~45%) exhibit TDP-43 positive neuronal inclusions, suggesting a role for this protein in disease pathogenesis. In addition, TDP-43 inclusions are evident in familial ALS phenotypes linked to multiple gene mutations including the

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Ortiz, Genaro Gabriel, Javier Ramírez-Jirano, Raul L. Arizaga, Daniela L. C. Delgado-Lara, and Erandis D. Torres-Sánchez. "Frontotemporal-TDP and LATE Neurocognitive Disorders: A Pathophysiological and Genetic Approach." Brain Sciences 13, no. 10 (2023): 1474. http://dx.doi.org/10.3390/brainsci13101474.

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Frontotemporal lobar degeneration (FTLD) belongs to a heterogeneous group of highly complex neurodegenerative diseases and represents the second cause of presenile dementia in individuals under 65. Frontotemporal-TDP is a subgroup of frontotemporal dementia characterized by the aggregation of abnormal protein deposits, predominantly transactive response DNA-binding protein 43 (TDP-43), in the frontal and temporal brain regions. These deposits lead to progressive degeneration of neurons resulting in cognitive and behavioral impairments. Limbic age-related encephalopathy (LATE) pertains to age-r

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Fletcher, Phillip, Jonathan Schott, Martin Rossor, and Jason Warren. "ABNORMAL SOUND AND MUSIC REWARD PROCESSING IN DEMENTIA: A BEHAVIOURAL AND NEUROANATOMICAL ANALYSIS." Journal of Neurology, Neurosurgery & Psychiatry 86, no. 11 (2015): e4.136-e4. http://dx.doi.org/10.1136/jnnp-2015-312379.46.

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Patients with dementia may exhibit abnormally altered liking for environmental sounds and music but such altered auditory hedonic responses have not been studied systematically. Here we addressed this issue in a cohort of 73 patients representing major canonical dementia syndromes (behavioural variant frontotemporal dementia (bvFTD), semantic dementia (SD), progressive nonfluent aphasia (PNFA) amnestic Alzheimer's disease (AD)) using a semi-structured caregiver behavioural questionnaire and voxel-based morphometry of patients' brain MR images. Behavioural responses signalling abnormal aversion

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Massano, João, Miguel Leão, Carolina Garrett, and On behalf of Grupo de Neurogenética do Centro Hospitalar São João. "Investigação de Etiologia Genética nas Demências Neurodegenerativas: Recomendações do Grupo de Neurogenética do Centro Hospitalar São João." Acta Médica Portuguesa 29, no. 10 (2016): 675. http://dx.doi.org/10.20344/amp.7583.

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In the past few years several gene mutations have been identified as causative of the most frequent neurodegenerative dementias (Alzheimer disease and frontotemporal dementia). These advances, along with the complex phenotype-genotype relationships and the costs associated with genetic testing, have often made it difficult for clinicians to decide with regard to a rational plan for the investigation of the genetic etiology of the degenerative dementias. The Centro Hospitalar São João Neurogenetics Group, a multidisciplinary team of Neurologists and Geneticists with special interest in neurogen

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Bono, Nina, Flaminia Fruzzetti, Giorgia Farinazzo, Gabriele Candiani, and Stefania Marcuzzo. "Perspectives in Amyotrophic Lateral Sclerosis: Biomarkers, Omics, and Gene Therapy Informing Disease and Treatment." International Journal of Molecular Sciences 26, no. 12 (2025): 5671. https://doi.org/10.3390/ijms26125671.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons, leading to muscle weakness, paralysis, and ultimately respiratory failure. Despite advances in understanding its genetic basis, particularly mutations in Chromosome 9 Open Reading Frame 72 (C9orf72), superoxide dismutase 1 (SOD1), TAR DNA-binding protein (TARDBP), and Fused in Sarcoma (FUS) gene, current diagnostic methods result in delayed intervention, and available treatments offer only modest benefits. This review examines innovative approaches tr

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Skaar, Jeffrey R., Derek J. Richard, Anita Saraf, et al. "INTS3 controls the hSSB1-mediated DNA damage response." Journal of Cell Biology 187, no. 1 (2009): 25–32. http://dx.doi.org/10.1083/jcb.200907026.

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Human SSB1 (single-stranded binding protein 1 [hSSB1]) was recently identified as a part of the ataxia telangiectasia mutated (ATM) signaling pathway. To investigate hSSB1 function, we performed tandem affinity purifications of hSSB1 mutants mimicking the unphosphorylated and ATM-phosphorylated states. Both hSSB1 mutants copurified a subset of Integrator complex subunits and the uncharacterized protein LOC58493/c9orf80 (henceforth minute INTS3/hSSB-associated element [MISE]). The INTS3–MISE–hSSB1 complex plays a key role in ATM activation and RAD51 recruitment to DNA damage foci during the res

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Wallace, Amelia D., Thomas A. Sasani, Jordan Swanier, et al. "CaBagE: A Cas9-based Background Elimination strategy for targeted, long-read DNA sequencing." PLOS ONE 16, no. 4 (2021): e0241253. http://dx.doi.org/10.1371/journal.pone.0241253.

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A substantial fraction of the human genome is difficult to interrogate with short-read DNA sequencing technologies due to paralogy, complex haplotype structures, or tandem repeats. Long-read sequencing technologies, such as Oxford Nanopore’s MinION, enable direct measurement of complex loci without introducing many of the biases inherent to short-read methods, though they suffer from relatively lower throughput. This limitation has motivated recent efforts to develop amplification-free strategies to target and enrich loci of interest for subsequent sequencing with long reads. Here, we present

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Leray, Xavier, Rossella Conti, Yan Li, et al. "Arginine-selective modulation of the lysosomal transporter PQLC2 through a gate-tuning mechanism." Proceedings of the National Academy of Sciences 118, no. 32 (2021): e2025315118. http://dx.doi.org/10.1073/pnas.2025315118.

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Lysosomes degrade excess or damaged cellular components and recycle their building blocks through membrane transporters. They also act as nutrient-sensing signaling hubs to coordinate cell responses. The membrane protein PQ-loop repeat-containing protein 2 (PQLC2; “picklock two”) is implicated in both functions, as it exports cationic amino acids from lysosomes and serves as a receptor and amino acid sensor to recruit the C9orf72/SMCR8/WDR41 complex to lysosomes upon nutrient starvation. Its transport activity is essential for drug treatment of the rare disease cystinosis. Here, we quantitativ

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Scholz, Sonja W., and Inma Cobos. "Genetics and Neuropathology of Neurodegenerative Dementias." CONTINUUM: Lifelong Learning in Neurology 30, no. 6 (2024): 1801–22. https://doi.org/10.1212/con.0000000000001505.

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ABSTRACT OBJECTIVE This article provides an overview of the current understanding of the genetic and pathologic features of neurodegenerative dementias, with an emphasis on Alzheimer disease and related dementias. LATEST DEVELOPMENTS In recent years, there has been substantial progress in genetic research, contributing significant knowledge to our understanding of the molecular risk factors involved in neurodegenerative dementia syndromes. Several genes have been linked to monogenic forms of dementia (eg, APP, PSEN1, PSEN2, SNCA, GRN, C9orf72, MAPT) and an even larger number of genetic variant

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Božič, Tim, Matja Zalar, Boris Rogelj, Janez Plavec, and Primož Šket. "Structural Diversity of Sense and Antisense RNA Hexanucleotide Repeats Associated with ALS and FTLD." Molecules 25, no. 3 (2020): 525. http://dx.doi.org/10.3390/molecules25030525.

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The hexanucleotide expansion GGGGCC located in C9orf72 gene represents the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). Since the discovery one of the non-exclusive mechanisms of expanded hexanucleotide G4C2 repeats involved in ALS and FTLD is RNA toxicity, which involves accumulation of pathological sense and antisense RNA transcripts. Formed RNA foci sequester RNA-binding proteins, causing their mislocalization and, thus, diminishing their biological function. Therefore, structures adopted by pathological RNA transcripts could hav

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Amador, Maria-Del-Mar, François Muratet, Elisa Teyssou, et al. "Spastic paraplegia due to recessive or dominant mutations in ERLIN2 can convert to ALS." Neurology Genetics 5, no. 6 (2019): e374. http://dx.doi.org/10.1212/nxg.0000000000000374.

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ObjectiveThe aim of this study was to evaluate whether mutations in ERLIN2, known to cause SPG18, a recessive hereditary spastic paraplegia (SP) responsible for the degeneration of the upper motor neurons leading to weakness and spasticity restricted to the lower limbs, could contribute to amyotrophic lateral sclerosis (ALS), a distinct and more severe motor neuron disease (MND), in which the lower motor neurons also profusely degenerates, leading to tetraplegia, bulbar palsy, respiratory insufficiency, and ultimately the death of the patients.MethodsWhole-exome sequencing was performed in a l

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Tang, Dan, Kaixuan Zheng, Jiangli Zhu, et al. "ALS-linked C9orf72–SMCR8 complex is a negative regulator of primary ciliogenesis." Proceedings of the National Academy of Sciences 120, no. 50 (2023). http://dx.doi.org/10.1073/pnas.2220496120.

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Massive GGGGCC (G4C2) repeat expansion in C9orf72 and the resulting loss of C9orf72 function are the key features of ~50% of inherited amyotrophic lateral sclerosis and frontotemporal dementia cases. However, the biological function of C9orf72 remains unclear. We previously found that C9orf72 can form a stable GTPase activating protein (GAP) complex with SMCR8 (Smith-Magenis chromosome region 8). Herein, we report that the C9orf72–SMCR8 complex is a major negative regulator of primary ciliogenesis, abnormalities in which lead to ciliopathies. Mechanistically, the C9orf72–SMCR8 complex suppress

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Amick, Joseph, Arun Kumar Tharkeshwar, Gabriel Talaia, and Shawn M. Ferguson. "PQLC2 recruits the C9orf72 complex to lysosomes in response to cationic amino acid starvation." Journal of Cell Biology 219, no. 1 (2019). http://dx.doi.org/10.1083/jcb.201906076.

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The C9orf72 protein is required for normal lysosome function. In support of such functions, C9orf72 forms a heterotrimeric complex with SMCR8 and WDR41 that is recruited to lysosomes when amino acids are scarce. These properties raise questions about the identity of the lysosomal binding partner of the C9orf72 complex and the amino acid–sensing mechanism that regulates C9orf72 complex abundance on lysosomes. We now demonstrate that an interaction with the lysosomal cationic amino acid transporter PQLC2 mediates C9orf72 complex recruitment to lysosomes. This is achieved through an interaction b

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Xiao, Shangxi, Paul M. McKeever, Agnes Lau, and Janice Robertson. "Synaptic localization of C9orf72 regulates post-synaptic glutamate receptor 1 levels." Acta Neuropathologica Communications 7, no. 1 (2019). http://dx.doi.org/10.1186/s40478-019-0812-5.

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Abstract A hexanucleotide repeat expansion in a noncoding region of C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Reduction of select or total C9orf72 transcript and protein levels is observed in postmortem C9-ALS/FTD tissue, and loss of C9orf72 orthologues in zebrafish and C. elegans results in motor deficits. However, how the reduction in C9orf72 in ALS and FTD might contribute to the disease process remains poorly understood. It has been shown that C9orf72 interacts and forms a complex with SMCR8 and WDR41, acting as a gua

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Zhang, Shen, Mindan Tong, Denghao Zheng, et al. "C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediated membrane tethering and fusion in mammalian autophagy." Nature Communications 14, no. 1 (2023). http://dx.doi.org/10.1038/s41467-023-42003-0.

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AbstractThe multi-subunit homotypic fusion and vacuole protein sorting (HOPS) membrane-tethering complex is required for autophagosome-lysosome fusion in mammals, yet reconstituting the mammalian HOPS complex remains a challenge. Here we propose a “hook-up” model for mammalian HOPS complex assembly, which requires two HOPS sub-complexes docking on membranes via membrane-associated Rabs. We identify Rab39A as a key small GTPase that recruits HOPS onto autophagic vesicles. Proper pairing with Rab2 and Rab39A enables HOPS complex assembly between proteoliposomes for its tethering function, facili

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Su, Ming-Yuan, Simon A. Fromm, Jonathan Remis, Daniel B. Toso, and James H. Hurley. "Structural basis for the ARF GAP activity and specificity of the C9orf72 complex." Nature Communications 12, no. 1 (2021). http://dx.doi.org/10.1038/s41467-021-24081-0.

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AbstractMutation of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontal temporal degeneration (FTD), which is attributed to both a gain and loss of function. C9orf72 forms a complex with SMCR8 and WDR41, which was reported to have GTPase activating protein activity toward ARF proteins, RAB8A, and RAB11A. We determined the cryo-EM structure of ARF1-GDP-BeF3- bound to C9orf72:SMCR8:WDR41. The SMCR8longin and C9orf72longin domains form the binding pocket for ARF1. One face of the C9orf72longin domain holds ARF1 in place, while the SMCR8longin positions the

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Coyne, Alyssa N., and Jeffrey D. Rothstein. "Nuclear lamina invaginations are not a pathological feature of C9orf72 ALS/FTD." Acta Neuropathologica Communications 9, no. 1 (2021). http://dx.doi.org/10.1186/s40478-021-01150-5.

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AbstractThe most common genetic cause of familial and sporadic amyotrophic lateral sclerosis (ALS) is a GGGGCC hexanucleotide repeat expansion (HRE) in the C9orf72 gene. While direct molecular hallmarks of the C9orf72 HRE (repeat RNA foci, dipeptide repeat protein pathology) are well characterized, the mechanisms by which the C9orf72 HRE causes ALS and the related neurodegenerative disease frontotemporal dementia (FTD) remain poorly understood. Recently, alterations to the nuclear pore complex and nucleocytoplasmic transport have been accepted as a prominent pathomechanism underlying C9orf72 A

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Jo, Yunhee, Jiwon Lee, Seul-Yi Lee, Ilmin Kwon, and Hana Cho. "Poly-dipeptides produced from C9orf72 hexanucleotide repeats cause selective motor neuron hyperexcitability in ALS." Proceedings of the National Academy of Sciences 119, no. 11 (2022). http://dx.doi.org/10.1073/pnas.2113813119.

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Significance The GGGGCC hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 ( C9orf72 ) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS). Despite myriad studies on the toxic effects of poly-dipeptides produced from the C9orf72 repeats, the mechanisms underlying the selective hyperexcitability of motor cortex that characterizes the early stages of C9orf72 ALS patients remain elusive. Here, we show that the proline–arginine poly-dipeptides cause hyperexcitability in cortical motor neurons by increasing persistent sodium currents conducted by the

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Nishimura, Agnes L., and Natalia Arias. "Synaptopathy Mechanisms in ALS Caused by C9orf72 Repeat Expansion." Frontiers in Cellular Neuroscience 15 (June 1, 2021). http://dx.doi.org/10.3389/fncel.2021.660693.

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Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disease caused by degeneration of motor neurons (MNs). ALS pathogenic features include accumulation of misfolded proteins, glutamate excitotoxicity, mitochondrial dysfunction at distal axon terminals, and neuronal cytoskeleton changes. Synergies between loss of C9orf72 functions and gain of function by toxic effects of repeat expansions also contribute to C9orf72-mediated pathogenesis. However, the impact of haploinsufficiency of C9orf72 on neurons and in synaptic functions requires further examination. As the motor neurons deg

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Dickson, Dennis W., Matthew C. Baker, Jazmyne L. Jackson, et al. "Extensive transcriptomic study emphasizes importance of vesicular transport in C9orf72 expansion carriers." Acta Neuropathologica Communications 7, no. 1 (2019). http://dx.doi.org/10.1186/s40478-019-0797-0.

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Abstract The majority of the clinico-pathological variability observed in patients harboring a repeat expansion in the C9orf72-SMCR8 complex subunit (C9orf72) remains unexplained. This expansion, which represents the most common genetic cause of frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND), results in a loss of C9orf72 expression and the generation of RNA foci and dipeptide repeat (DPR) proteins. The C9orf72 protein itself plays a role in vesicular transport, serving as a guanine nucleotide exchange factor that regulates GTPases. To further elucidate the mechanisms u

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Viera Ortiz, Ashley P., Gregory Cajka, Olamide A. Olatunji, Bailey Mikytuck, Ophir Shalem, and Edward B. Lee. "Impaired ribosome-associated quality control of C9orf72 arginine-rich dipeptide-repeat proteins." Brain, December 14, 2022. http://dx.doi.org/10.1093/brain/awac479.

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Abstract Protein quality control pathways have evolved to ensure the fidelity of protein synthesis and efficiently clear potentially toxic protein species. Defects in ribosome-associated quality control and its associated factors have been implicated in the accumulation of aberrant proteins and neurodegeneration. C9orf72 repeat-associated non-AUG translation has been suggested to involve inefficient translation elongation, lead to ribosomal pausing and activation of ribosome-associated quality control pathways. However, the role of the ribosome-associated quality control complex in the process

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Azimian, Fereshteh, Yan‐Hua Chen, and Qun Lu. "Targeting the Interactions of Small GTPase ARF with C9ORF72:SMCR8:WDR41 Complexes Implicated in Amyotrophic Lateral Sclerosis/Frontotemporal Dementia." Alzheimer's & Dementia 19, S21 (2023). http://dx.doi.org/10.1002/alz.076804.

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AbstractBackgroundC9ORF72 plays important roles in many cellular processes, including autophagy, membrane trafficking and immune response. The C9ORF72 mutation is the most common cause of familial amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) which is attributed to both gain‐ and loss‐of‐function mechanisms. C9ORF72 forms a complex with SMCR8 and WDR41, which was reported to regulate signaling of small GTPases such as Rab and ARF proteins. Developing small molecules that modulate interfacial C9ORF72:SMCR8:WDR41 (CSW) and small GTPase interactions will aid in understanding the

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