@article{bbb48d0d43d3434cb1c604e326ce14e3,
title = "Hexanucleotide Repeat Expansions in c9FTD/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo",
abstract = "A G4C2 hexanucleotide repeat expansion in an intron of C9orf72 is the most common cause of frontal temporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). A remarkably similar intronic TG3C2 repeat expansion is associated with spinocerebellar ataxia 36 (SCA36). Both expansions are widely expressed, form RNA foci, and can undergo repeat-associated non-ATG (RAN) translation to form similar dipeptide repeat proteins (DPRs). Yet, these diseases result in the degeneration of distinct subsets of neurons. We show that the expression of these repeat expansions in mice is sufficient to recapitulate the unique features of each disease, including this selective neuronal vulnerability. Furthermore, only the G4C2 repeat induces the formation of aberrant stress granules and pTDP-43 inclusions. Overall, our results demonstrate that the pathomechanisms responsible for each disease are intrinsic to the individual repeat sequence, highlighting the importance of sequence-specific RNA-mediated toxicity in each disorder.",
keywords = "ALS, C9orf72, FTD, RAN translation, RNA foci, SCA36, TDP-43, mouse, poly(GP), poly(PR)",
author = "Todd, {Tiffany W.} and McEachin, {Zachary T.} and Jeannie Chew and Burch, {Alexander R.} and Karen Jansen-West and Jimei Tong and Mei Yue and Yuping Song and Monica Castanedes-Casey and Aishe Kurti and Dunmore, {Judith H.} and Fryer, {John D.} and Zhang, {Yong Jie} and {San Millan}, Beatriz and {Teijeira Bautista}, Susana and Manuel Arias and Dennis Dickson and Gendron, {Tania F.} and Sobrido, {Mar{\'i}a Jes{\'u}s} and Disney, {Matthew D.} and Bassell, {Gary J.} and Wilfried Rossoll and Leonard Petrucelli",
note = "Funding Information: We are grateful to all patients and their families who agreed to donate postmortem tissue. Human biological samples and associated data were obtained from the Emory Neuropathology Core ( P30 NS055077 ) and the Brain Bank of Biobank Galicia Sur Health Research Institute ( PT17/0015/0034 ) and were used in compliance with all ethical regulations set forth by these institutions. Informed consent was obtained from patients prior to the inclusion of samples in each bank. We would like to acknowledge all individuals who assisted in the procuring of these samples. This work was supported by the National Institutes of Health, National Institute of Neurological Disorder and Stroke (grants R35NS097273 , P01NS084974 , P01NS099114 , R01NS088689 , R35NS097263 , R01NS91749 , and R21NS084528 ), the National Institute of Environmental Health Sciences (grant R01ES20395 ), the Department of Defense (ALSRP grant AL130125 ), the Mayo Clinic Foundation , the Robert Packard Center for ALS Research at Johns Hopkins , Target ALS , an ALS Association Milton Safenowitz Postdoctoral Fellowship ( 17-PDF-361 to T.W.T.), and the Muscular Dystrophy Association (grant 426618 ). Funding Information: We are grateful to all patients and their families who agreed to donate postmortem tissue. Human biological samples and associated data were obtained from the Emory Neuropathology Core (P30 NS055077) and the Brain Bank of Biobank Galicia Sur Health Research Institute (PT17/0015/0034) and were used in compliance with all ethical regulations set forth by these institutions. Informed consent was obtained from patients prior to the inclusion of samples in each bank. We would like to acknowledge all individuals who assisted in the procuring of these samples. This work was supported by the National Institutes of Health, National Institute of Neurological Disorder and Stroke (grants R35NS097273, P01NS084974, P01NS099114, R01NS088689, R35NS097263, R01NS91749, and R21NS084528), the National Institute of Environmental Health Sciences (grant R01ES20395), the Department of Defense (ALSRP grant AL130125), the Mayo Clinic Foundation, the Robert Packard Center for ALS Research at Johns Hopkins, Target ALS, an ALS Association Milton Safenowitz Postdoctoral Fellowship (17-PDF-361 to T.W.T.), and the Muscular Dystrophy Association (grant 426618). T.W.T. carried out experiments and characterized the TG3C2 mice. T.W.T. W.R. and L.P. designed experiments. Z.T.M. M.-J.S. G.J.B. and W.R. coordinated human sample collection. Z.T.M. M.C.-C. and D.D. performed IHC on patient tissues. J.C. characterized the G4C2 mice. K.J.-W. made constructs. J.T. aided in mouse husbandry and harvests. M.Y. and J.H.D. performed intracerebroventricular (i.c.v.) injections. A.K. T.W.T. and J.D.F. performed behavioral analyses. T.W.T. performed cell culture, IF, and FISH. T.F.G. performed MSD immunoassays. Y.-J.Z. T.W.T. M.C.-C. A.R.B. and D.D. performed IHC on mouse tissue. M.-J.S. M.A. B.S.M. and S.T.B. provided patient samples and genetic and clinical data. A.R.B. and Y.S. provided technical support. T.W.T. wrote the manuscript. T.W.T. L.P. W.R. and M.D.D. revised and edited the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = may,
day = "5",
doi = "10.1016/j.celrep.2020.107616",
language = "English (US)",
volume = "31",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}