ArticleNeuron2020
Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36.
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Article in Neuron, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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48 citing papers in PubMed, 75 citations in OpenAlex.
- Insights into X-linked Dystonia-Parkinsonism and Spinocerebellar Ataxia type 36 Through the Lens of Amyotrophic Lateral Sclerosis/Frontotemporal Dementia.Molecular neurobiology · 2026Review
- Upstream non-AUG initiation and ribosomal -1 frameshifting in ATXN8OS CTA/CTG repeat-associated translation.Nucleic acids research · 2026Article
- NOP56 is essential for mammalian generation and maintenance of multiple central nervous systems, associated with SCA36 pathology.Acta neuropathologica communications · 2026Article
- Blocking RAN translation without altering repeat RNAs rescuesScience (New York, N.Y.) · 2026Article
- A fly model of SCA36 reveals combinatorial neurotoxicity of hexanucleotide and dipeptide repeats.PLoS genetics · 2025Article
- Aberrant splicing exonizes C9orf72 repeat expansion in ALS/FTD.Nature neuroscience · 2025Article
- Canonical translation factors eIF1A and eIF5B modulate the initiation step of repeat-associated non-AUG translation.Nucleic acids research · 2025Article
- Limited Myelination Capacity in Human Schwann Cells in Experimental Models in Comparison to Rodent and Porcine Schwann Cells.International journal of molecular sciences · 2025Article
- pTDP-43 levels correlate with cell type-specific molecular alterations in the prefrontal cortex ofProceedings of the National Academy of Sciences of the United States of America · 2025Article
- RNA dysregulation in neurodegenerative diseases.The EMBO journal · 2025Review
- Hippocampal aggregation signatures of pathogenic UBQLN2 in amyotrophic lateral sclerosis and frontotemporal dementia.Brain : a journal of neurology · 2024Article
- pTDP-43 levels correlate with cell type specific molecular alterations in the prefrontal cortex ofbioRxiv : the preprint server for biology · 2024Article
- CAG repeat expansions create splicing acceptor sites and produce aberrant repeat-containing RNAs.Molecular cell · 2024Article
- Reconstitution of C9orf72 GGGGCC repeat-associated non-AUG translation with purified human translation factors.Scientific reports · 2023Article
- CAG repeat expansions create splicing acceptor sites and produce aberrant repeat-containing RNAs.bioRxiv : the preprint server for biology · 2023Article
- Single-molecule imaging reveals distinct elongation and frameshifting dynamics between frames of expanded RNA repeats in C9ORF72-ALS/FTD.Nature communications · 2023Article
- Repeat length of C9orf72-associated glycine-alanine polypeptides affects their toxicity.Acta neuropathologica communications · 2023Article
- Translation dysregulation in neurodegenerative diseases: a focus on ALS.Molecular neurodegeneration · 2023Review
- Impaired ribosome-associated quality control of C9orf72 arginine-rich dipeptide-repeat proteins.Brain : a journal of neurology · 2023Article
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Authors and funding
36 authors at 12 institutions in 4 countries.
Zachary T McEachinDepartment of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Wallace H. Coulter Graduate Program in Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332, USA. Electronic address: zmceach@emory.edu.
Tania F GendronDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA.
Nisha RajDepartment of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA.
María García-MuriasCentro de Investigación Biomédica en red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain; Neurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
Anwesha BanerjeeDepartment of Cell Biology, Emory University, Atlanta, GA 30322, USA.
Ryan H PurcellDepartment of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA.
Patricia J WardDepartment of Cell Biology, Emory University, Atlanta, GA 30322, USA.
Tiffany W ToddDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Megan E Merritt-GarzaLaboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA.
Karen Jansen-WestDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Chadwick M HalesDepartment of Neurology, Emory University, Atlanta, GA 30322, USA.
Tania García-SobrinoDepartment of Neurology, Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
Beatriz QuintánsCentro de Investigación Biomédica en red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain; Neurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
Christopher J HollerDepartment of Pharmacology & Chemical Biology, Emory University, Atlanta, GA 30322, USA.
Georgia TaylorDepartment of Pharmacology & Chemical Biology, Emory University, Atlanta, GA 30322, USA.
Beatriz San MillánRare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain; Pathology Department, Complexo Hospitalario Universitario de Vigo (CHUVI), SERGAS, Vigo, Spain.
Susana TeijeiraRare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain; Pathology Department, Complexo Hospitalario Universitario de Vigo (CHUVI), SERGAS, Vigo, Spain.
Toru YamashitaDepartment of Neurology, Okayama University, Okayama, Japan.
Ryuichi OhkuboDepartment of Neurology, Fujimoto General Hospital, Miyazaki, Japan.
Nicholas M BoulisDepartment of Neurosurgery, Emory University, Atlanta, GA 30322, USA.
Chongchong XuDepartment of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA 30322, USA.
Zhexing WenDepartment of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Department of Neurology, Emory University, Atlanta, GA 30322, USA; Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA 30322, USA.
Nathalie StreichenbergerHospices Civils de Lyon, Lyon, France; Université Claude Bernard Lyon, Lyon, France; Institut NeuroMyogène CNRS UMR 5310.
Neuro–CEB Neuropathology Network
Brent L FogelDepartment of Neurology & Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Thomas KukarDepartment of Neurology, Emory University, Atlanta, GA 30322, USA; Department of Pharmacology & Chemical Biology, Emory University, Atlanta, GA 30322, USA.
Koji AbeDepartment of Neurology, Okayama University, Okayama, Japan.
Dennis W DicksonDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Manuel AriasNeurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain; Department of Neurology, Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
Jonathan D GlassDepartment of Neurology, Emory University, Atlanta, GA 30322, USA.
Jie JiangDepartment of Cell Biology, Emory University, Atlanta, GA 30322, USA.
Malú G TanseyDepartment of Neuroscience, University of Florida, Gainesville, FL 32607, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32607, USA; Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL 32607, USA.
María-Jesús SobridoCentro de Investigación Biomédica en red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain; Neurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
Leonard PetrucelliDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA.
Wilfried RossollDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA.
Gary J BassellDepartment of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Wallace H. Coulter Graduate Program in Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332, USA; Department of Neurology, Emory University, Atlanta, GA 30322, USA. Electronic address: gbassel@emory.edu.
Emory University · USCentre for Biomedical Network Research on Rare Diseases · ESJacksonville College · USMayo Clinic in Florida · USComplejo Hospitalario Universitario de Santiago · ESGeorgia Institute of Technology · USOkayama University · JPUniversity Hospital Complex Of Vigo · ESFujieda Municipal General Hospital · JPUniversité Claude Bernard Lyon 1 · FRUniversity of California, Los Angeles · USUniversity of Florida · US
Funding
The Goizueta Alzheimer's Disease Research CenterP30AG066511 · NIA · EMORY UNIVERSITY · PI ALLAN I LEVEY · 2020 to 2026
$29.0MThe Emory Alzheimer's Disease CenterP50AG025688 · NIA · EMORY UNIVERSITY · PI WALKER, LARY C · 2005 to 2019
$25.7MProject 3: Neuropathology of the multi-proteinopathy of c9FTD/ALS.P01NS084974 · NINDS · MAYO CLINIC JACKSONVILLE · PI PETRUCELLI, LEONARD · 2014 to 2024
$17.6MExpanding insights into FTD disease mechanismsR35NS097273 · NINDS · MAYO CLINIC JACKSONVILLE · PI PETRUCELLI, LEONARD · 2017 to 2024
$10.6MENNCF - Viral Vector CoreP30NS055077 · NINDS · EMORY UNIVERSITY · PI LEVEY, ALLAN I · 2008 to 2018
$6.8MValidation of r(G4C2)exp-binding small molecules in vivo and c9FTD/ALS biomarker developmentP01NS099114 · NINDS · UNIVERSITY OF FLORIDA · PI ROTHSTEIN, JEFFREY D · 2017 to 2021
$6.5MTRAINING IN TRANSLATIONAL RESEARCH IN NEUROLOGYT32NS007480 · NINDS · EMORY UNIVERSITY · PI LEVEY, ALLAN I · 2000 to 2020
$4.5MRNA Processing Defects in SMA and Their Contribution to the Disease PhenotypeR01NS091749 · NINDS · MAYO CLINIC JACKSONVILLE · PI ROSSOLL, WILFRIED · 2015 to 2019
$1.9MMolecular mechanisms of Progranulin in NeurodegenerationR01NS105971 · NINDS · EMORY UNIVERSITY · PI KUKAR, THOMAS L · 2018 to 2022
$1.9MDefining the role of FUS phosphorylation in neurodegenerationR01NS093362 · NINDS · EMORY UNIVERSITY · PI KUKAR, THOMAS L · 2015 to 2019
$1.7MRare and Novel Genetic Variation in the Pathogenesis of Cerebellar AtaxiaR01NS082094 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI FOGEL, BRENT LINDEN · 2013 to 2017
$1.7MSelective modulation of Gamma-secretase processing through substrate bindingR00AG032362 · NIA · EMORY UNIVERSITY · PI KUKAR, THOMAS L · 2012 to 2014
$713kNIA NIH HHS K99 AG032362NIA NIH HHS P30 AG066511NIA NIH HHS P50 AG025688NIA NIH HHS R00 AG032362NINDS NIH HHS P01 NS084974NINDS NIH HHS P01 NS099114NINDS NIH HHS P30 NS055077NINDS NIH HHS R01 NS082094NINDS NIH HHS R01 NS091749NINDS NIH HHS R01 NS093362NINDS NIH HHS R01 NS105971NINDS NIH HHS R21 NS114908NINDS NIH HHS R35 NS097273NINDS NIH HHS T32 NS007480
Abstract
GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and lead to the production of aggregating dipeptide repeat proteins (DPRs) via repeat associated non-AUG (RAN) translation. Here, we show the similar intronic GGCCTG HREs that causes spinocerebellar ataxia type 36 (SCA36) is also translated into DPRs, including poly(GP) and poly(PR). We demonstrate that poly(GP) is more abundant in SCA36 compared to c9ALS/FTD patient tissue due to canonical AUG-mediated translation from intron-retained GGCCTG repeat RNAs. However, the frequency of the antisense RAN translation product poly(PR) is comparable between c9ALS/FTD and SCA36 patient samples. Interestingly, in SCA36 patient tissue, poly(GP) exists as a soluble species, and no TDP-43 pathology is present. We show that aggregate-prone chimeric DPR (cDPR) species underlie the divergent DPR pathology between c9ALS/FTD and SCA36. These findings reveal key differences in translation, solubility, and protein aggregation of DPRs between c9ALS/FTD and SCA36.
Indexed as
Amino Acid SequenceAmyotrophic Lateral SclerosisAnimalsAnimals, NewbornAntisense Elements (Genetics)C9orf72 ProteinDipeptidesDNA Repeat ExpansionFemaleFrontotemporal DementiaHumansIntronsMiceMice, Inbred C57BLMutant Chimeric ProteinsPregnancyAntisense Elements (Genetics)C9orf72 ProteinC9orf72 protein, humanDipeptidesMutant Chimeric ProteinsALSantisense oligonucleotide therapyC9orf72 expansionchimeric DPRsdipeptide repeatsFTDneurodegenerationRAN translationSCA36
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