C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD
Elaine Liu,Jenny Russ,Kathryn Wu,Donald E. Neal,EunRan Suh,Anna G. McNally,David J. Irwin,Vivianna M. Van Deerlin,Edward B. Lee +8 more
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Results indicate that C9orf72 promoter hypermethylation prevents downstream molecular aberrations associated with the hexanucleotide repeat expansion, suggesting that epigenetic silencing of the mutant C9orc72 allele may represent a protective counter-regulatory response to hexan nucleotide repeat Expansion.Abstract:
Hexanucleotide repeat expansions of C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal degeneration. The mutation is associated with reduced C9orf72 expression and the accumulation of potentially toxic RNA and protein aggregates. CpG methylation is known to protect the genome against unstable DNA elements and to stably silence inappropriate gene expression. Using bisulfite cloning and restriction enzyme-based methylation assays on DNA from human brain and peripheral blood, we observed CpG hypermethylation involving the C9orf72 promoter in cis to the repeat expansion mutation in approximately one-third of C9orf72 repeat expansion mutation carriers. Promoter hypermethylation of mutant C9orf72 was associated with transcriptional silencing of C9orf72 in patient-derived lymphoblast cell lines, resulting in reduced accumulation of intronic C9orf72 RNA and reduced numbers of RNA foci. Furthermore, demethylation of mutant C9orf72 with 5-aza-deoxycytidine resulted in increased vulnerability of mutant cells to oxidative and autophagic stress. Promoter hypermethylation of repeat expansion carriers was also associated with reduced accumulation of RNA foci and dipeptide repeat protein aggregates in human brains. These results indicate that C9orf72 promoter hypermethylation prevents downstream molecular aberrations associated with the hexanucleotide repeat expansion, suggesting that epigenetic silencing of the mutant C9orf72 allele may represent a protective counter-regulatory response to hexanucleotide repeat expansion.read more
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Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs
Jie Jiang,Jie Jiang,Qiang Zhu,Tania F. Gendron,Shahram Saberi,Melissa McAlonis-Downes,Amanda Seelman,Jennifer E. Stauffer,Paymaan Jafar-Nejad,Kevin Drenner,Derek Schulte,Seung J. Chun,Shuying Sun,Shuo-Chien Ling,Shuo-Chien Ling,Brian Myers,Jeffery Engelhardt,Melanie Katz,Michael Baughn,Michael Baughn,Oleksandr Platoshyn,Oleksandr Platoshyn,Martin Marsala,Martin Marsala,Martin Marsala,Andrew T. Watt,Charles J. Heyser,M. Colin Ard,Louis De Muynck,Lillian M. Daughrity,Deborah A. Swing,Lino Tessarollo,Chris J. Jung,Arnaud Delpoux,Daniel T. Utzschneider,Stephen M. Hedrick,Pieter J. de Jong,Dieter Edbauer,Philip Van Damme,Leonard Petrucelli,Christopher Shaw,C. Frank Bennett,Sandrine Da Cruz,John Ravits,Frank Rigo,Don W. Cleveland,Don W. Cleveland,Clotilde Lagier-Tourenne,Clotilde Lagier-Tourenne +48 more
TL;DR: Single-dose injection of antisense oligonucleotides (ASOs) that target repeat-containing RNAs but preserve levels of mRNAs encoding C9ORF72 produced sustained reductions in RNA foci and dipeptide-repeat proteins, and ameliorated behavioral deficits.
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C9orf72 -mediated ALS and FTD: multiple pathways to disease
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TL;DR: It is suggested that a combination of upstream mechanisms involving both loss and gain of function and downstream cellular pathways involving both cell-aut autonomous and non-cell-autonomous effects contributes to disease progression.
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Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons.
Yingxiao Shi,Shaoyu Lin,Kim A. Staats,Yichen Li,Wen-Hsuan Chang,Shu Ting Hung,Eric Hendricks,Gabriel R. Linares,Yaoming Wang,Esther Y. Son,Xinmei Wen,Kassandra Kisler,Brent Wilkinson,Louise Menendez,Tohru Sugawara,Phillip E. Woolwine,Mickey Huang,Michael J. Cowan,Brandon B Ge,Nicole Koutsodendris,Kaitlin P. Sandor,Jacob Komberg,Vamshidhar R. Vangoor,Ketharini Senthilkumar,Valerie Hennes,Carina Seah,Amy R. Nelson,Tze-Yuan Cheng,Shih Jong J. Lee,Paul R. August,Jason A. Chen,N. Wisniewski,Victor Hanson-Smith,T. Grant Belgard,Alice Zhang,Marcelo P. Coba,Chris Grunseich,Michael E. Ward,Leonard H. van den Berg,R. Jeroen Pasterkamp,Davide Trotti,Berislav V. Zlokovic,Justin K. Ichida +42 more
Abstract: An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the pathogenic mechanism of this repeat remains unclear Using human induced motor neurons (iMNs), we found that repeat-expanded C9ORF72 was haploinsufficient in ALS We found that C9ORF72 interacted with endosomes and was required for normal vesicle trafficking and lysosomal biogenesis in motor neurons Repeat expansion reduced C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors, leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion Thus, cooperativity between gain- and loss-of-function mechanisms led to neurodegeneration Restoring C9ORF72 levels or augmenting its function with constitutively active RAB5 or chemical modulators of RAB5 effectors rescued patient neuron survival and ameliorated neurodegenerative processes in both gain- and loss-of-function C9ORF72 mouse models Thus, modulating vesicle trafficking was able to rescue neurodegeneration caused by the C9ORF72 repeat expansion Coupled with rare mutations in ALS2, FIG4, CHMP2B, OPTN and SQSTM1, our results reveal mechanistic convergence on vesicle trafficking in ALS and FTD
References
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Journal ArticleDOI
Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
Mariely DeJesus-Hernandez,Ian R. A. Mackenzie,Bradley F. Boeve,Adam L. Boxer,Matt Baker,Nicola J. Rutherford,Alexandra M. Nicholson,Ni Cole A. Finch,Heather C. Flynn,Jennifer Adamson,Naomi Kouri,Aleksandra Wojtas,Pheth Sengdy,Ging-Yuek Robin Hsiung,Anna Karydas,William W. Seeley,Keith A. Josephs,Giovanni Coppola,Daniel H. Geschwind,Zbigniew K. Wszolek,Howard Feldman,Howard Feldman,David S. Knopman,Ronald C. Petersen,Bruce L. Miller,Dennis W. Dickson,Kevin B. Boylan,Neill R. Graff-Radford,Rosa Rademakers +28 more
TL;DR: It is found that repeat expansion in C9ORF72 is a major cause of both FTD and ALS, suggesting multiple disease mechanisms.
Journal ArticleDOI
A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD
Alan E. Renton,Elisa Majounie,Adrian James Waite,Javier Simón-Sánchez,Javier Simón-Sánchez,Sara Rollinson,J. Raphael Gibbs,J. Raphael Gibbs,Jennifer C. Schymick,Hannu Laaksovirta,John C. van Swieten,John C. van Swieten,Liisa Myllykangas,Hannu Kalimo,Anders Paetau,Yevgeniya Abramzon,Anne M. Remes,Alice Kaganovich,Sonja W. Scholz,Sonja W. Scholz,Sonja W. Scholz,Jamie Duckworth,Jinhui Ding,Daniel W. Harmer,Dena G. Hernandez,Dena G. Hernandez,Janel O. Johnson,Janel O. Johnson,Kin Y. Mok,Mina Ryten,Danyah Trabzuni,Rita Guerreiro,Richard W. Orrell,James Neal,Alexandra Murray,J. P. Pearson,Iris E. Jansen,David Sondervan,Harro Seelaar,Derek J. Blake,Kate Young,Nicola Halliwell,Janis Bennion Callister,Greg Toulson,Anna Richardson,Alexander Gerhard,Julie S. Snowden,David M. A. Mann,David Neary,Mike A. Nalls,Terhi Peuralinna,Lilja Jansson,Veli-Matti Isoviita,Anna-Lotta Kaivorinne,Maarit Hölttä-Vuori,Elina Ikonen,Raimo Sulkava,Michael Benatar,Joanne Wuu,Adriano Chiò,Gabriella Restagno,Giuseppe Borghero,Mario Sabatelli,David Heckerman,Ekaterina Rogaeva,Lorne Zinman,Jeffrey D. Rothstein,Michael Sendtner,Carsten Drepper,Evan E. Eichler,Can Alkan,Ziedulla Abdullaev,Svetlana Pack,Amalia Dutra,Evgenia Pak,John Hardy,Andrew B. Singleton,Nigel Williams,Peter Heutink,Stuart Pickering-Brown,Huw R. Morris,Huw R. Morris,Huw R. Morris,Pentti J. Tienari,Bryan J. Traynor,Bryan J. Traynor +85 more
TL;DR: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases, and a large hexanucleotide repeat expansion in the first intron of C9ORF72 is shown.
Journal ArticleDOI
Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis.
TL;DR: It is presented the case here that these two processes are intimately linked, with disease-initiated perturbation of either leading to further deviation of both protein and RNA homeostasis through a feedforward loop including cell-to-cell prion-like spread that may represent the mechanism for relentless disease progression.
Journal ArticleDOI
The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS
Kohji Mori,Shih-Ming Weng,Thomas Arzberger,Stephanie May,Kristin Rentzsch,Elisabeth Kremmer,Bettina Schmid,Bettina Schmid,Hans A. Kretzschmar,Marc Cruts,Christine Van Broeckhoven,Christian Haass,Christian Haass,Dieter Edbauer,Dieter Edbauer +14 more
TL;DR: It is found that characteristic intracellular inclusions of misfolded proteins define C9orf72 pathology, but the core proteins of the majority of inclusions are still unknown, and a new class of proteins links a common genetic mutation to the predominant pathology in certain neurodegenerative diseases.
Journal ArticleDOI
Unconventional Translation of C9ORF72 GGGGCC Expansion Generates Insoluble Polypeptides Specific to c9FTD/ALS
Peter E.A. Ash,Kevin F. Bieniek,Tania F. Gendron,Thomas R. Caulfield,Wen Lang Lin,Mariely DeJesus-Hernandez,Marka van Blitterswijk,Karen Jansen-West,Joseph W. Paul,Rosa Rademakers,Kevin B. Boylan,Dennis W. Dickson,Leonard Petrucelli +12 more
TL;DR: The specificity of C9RANT for c9FTD/ALS is a potential biomarker for this most common cause of FTD and ALS and have significant implications for treatment strategies directed at RAN-translated peptides and their aggregation and the RNA structures necessary for their production.
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