Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36.

Amino Acid Sequence Amyotrophic Lateral Sclerosis / genetics Animals Animals, Newborn Antisense Elements (Genetics) / genetics C9orf72 Protein / genetics DNA Repeat Expansion Dipeptides / genetics Female Frontotemporal Dementia / genetics Humans Introns / genetics Mice Mice, Inbred C57BL Mutant Chimeric Proteins / genetics Pregnancy Repetitive Sequences, Nucleic Acid Spinocerebellar Ataxias / genetics
ALS C9orf72 expansion FTD RAN translation SCA36 antisense oligonucleotide therapy chimeric DPRs dipeptide repeats neurodegeneration

Journal

Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320

Informations de publication

Date de publication:
22 07 2020
Historique:
received: 03 12 2019
revised: 11 03 2020
accepted: 06 04 2020
pubmed: 7 5 2020
medline: 21 10 2020
entrez: 7 5 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.neuron.2020.04.011 PMID: 32375063 PMC: PMC8138626
pubmed: 32375063
pii: S0896-6273(20)30280-4
doi: 10.1016/j.neuron.2020.04.011
pmc: PMC8138626
mid: NIHMS1612573
pii:
doi:

Substances chimiques

Antisense Elements (Genetics) 0
C9orf72 Protein 0
C9orf72 protein, human 0
Dipeptides 0
Mutant Chimeric Proteins 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

292-305.e6

Subventions

Organisme : NIA NIH HHS
ID : K99 AG032362
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS097273
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS105971
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS082094
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG066511
Pays : United States
Organisme : NIA NIH HHS
ID : P50 AG025688
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS091749
Pays : United States
Organisme : NINDS NIH HHS
ID : T32 NS007480
Pays : United States
Organisme : NIA NIH HHS
ID : R00 AG032362
Pays : United States
Organisme : NINDS NIH HHS
ID : P01 NS099114
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS114908
Pays : United States
Organisme : NINDS NIH HHS
ID : P30 NS055077
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS093362
Pays : United States
Organisme : NINDS NIH HHS
ID : P01 NS084974
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2020 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests The authors declare no competing interests.

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Auteurs

Zachary T McEachin (ZT)

Department 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 Gendron (TF)

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA.

Nisha Raj (N)

Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA.

María García-Murias (M)

Centro 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 Banerjee (A)

Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.

Ryan H Purcell (RH)

Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA.

Patricia J Ward (PJ)

Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.

Tiffany W Todd (TW)

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

Megan E Merritt-Garza (ME)

Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA.

Karen Jansen-West (K)

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

Chadwick M Hales (CM)

Department of Neurology, Emory University, Atlanta, GA 30322, USA.

Tania García-Sobrino (T)

Department of Neurology, Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.

Beatriz Quintáns (B)

Centro 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 Holler (CJ)

Department of Pharmacology & Chemical Biology, Emory University, Atlanta, GA 30322, USA.

Georgia Taylor (G)

Department of Pharmacology & Chemical Biology, Emory University, Atlanta, GA 30322, USA.

Beatriz San Millán (B)

Rare 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 Teijeira (S)

Rare 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 Yamashita (T)

Department of Neurology, Okayama University, Okayama, Japan.

Ryuichi Ohkubo (R)

Department of Neurology, Fujimoto General Hospital, Miyazaki, Japan.

Nicholas M Boulis (NM)

Department of Neurosurgery, Emory University, Atlanta, GA 30322, USA.

Chongchong Xu (C)

Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA 30322, USA.

Zhexing Wen (Z)

Department 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 Streichenberger (N)

Hospices Civils de Lyon, Lyon, France; Université Claude Bernard Lyon, Lyon, France; Institut NeuroMyogène CNRS UMR 5310.

Brent L Fogel (BL)

Department of Neurology & Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.

Thomas Kukar (T)

Department of Neurology, Emory University, Atlanta, GA 30322, USA; Department of Pharmacology & Chemical Biology, Emory University, Atlanta, GA 30322, USA.

Koji Abe (K)

Department of Neurology, Okayama University, Okayama, Japan.

Dennis W Dickson (DW)

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

Manuel Arias (M)

Neurogenetics 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 Glass (JD)

Department of Neurology, Emory University, Atlanta, GA 30322, USA.

Jie Jiang (J)

Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.

Malú G Tansey (MG)

Department 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 Sobrido (MJ)

Centro 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 Petrucelli (L)

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA.

Wilfried Rossoll (W)

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA.

Gary J Bassell (GJ)

Department 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.

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Classifications MeSH

questionsmedicales.fr › Sciences de l'information › Sources d'information › Services d'information › Documentation › Données de séquences moléculaires › Séquence d'acides aminés › Chimeric Peptide Species Contribute to...
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Troubles de l'homéostasie des protéines › Protéinopathies TDP-43 › Sclérose latérale amyotrophique › Chimeric Peptide Species Contribute to...
questionsmedicales.fr › Eucaryotes › Animaux › Chimeric Peptide Species Contribute to...
questionsmedicales.fr › Eucaryotes › Animaux › Groupes animaux › Animaux nouveau-nés › Chimeric Peptide Species Contribute to...
questionsmedicales.fr › Actions chimiques et utilisations › Utilisations spécialisées de produits chimiques › Produits chimiques de laboratoire › Sondes moléculaires › Sondes d'acide nucléique › Éléments antisens (génétique) › Chimeric Peptide Species Contribute to...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Régulateurs des protéines G › Facteurs d'échange de nucléotides guanyliques › Protéine C9orf72 › Chimeric Peptide Species Contribute to...
questionsmedicales.fr › Phénomènes génétiques › Mutagenèse › Expansion de séquence répétée de l'ADN › Chimeric Peptide Species Contribute to...
questionsmedicales.fr › Acides aminés, peptides et protéines › Peptides › Oligopeptides › Dipeptides › Chimeric Peptide Species Contribute to...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Démence › Dégénérescence lobaire frontotemporale › Démence frontotemporale › Chimeric Peptide Species Contribute to...
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questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Chimeric Peptide Species Contribute to...
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questionsmedicales.fr › Phénomènes physiologiques des appareils urinaire et reproducteur › Phénomènes physiologiques de la reproduction › Reproduction › Grossesse › Chimeric Peptide Species Contribute to...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Séquences répétées d'acides nucléiques › Chimeric Peptide Species Contribute to...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Maladies génétiques congénitales › Maladies neurodégénératives héréditaires › Dégénérescences spinocérébelleuses › Ataxies spinocérébelleuses › Chimeric Peptide Species Contribute to...