RPS25 is required for efficient RAN translation of C9orf72 and other neurodegenerative disease-associated nucleotide repeats

S.B. Yamada; T.F. Gendron; T. Niccoli; N.R. Genuth; R. Grosely; Y. Shi; I. Glaria; N.J. Kramer; L. Nakayama; S. Fang; T.J.I. Dinger; A. Thoeng; G. Rocha; M. Barna; J.D. Puglisi; L. Partridge; J.K. Ichida; A.M. Isaacs; L. Petrucelli; A.D. Gitler

doi:10.1038/s41593-019-0455-7

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Journal article

RPS25 is required for efficient RAN translation of C9orf72 and other neurodegenerative disease-associated nucleotide repeats

S.B. Yamada, T.F. Gendron, T. Niccoli, N.R. Genuth, R. Grosely, Y. Shi, I. Glaria, N.J. Kramer, L. Nakayama, S. Fang, …

Nature Neuroscience, Vol.22(9), pp.1383-1388

2019

DOI: https://doi.org/10.1038/s41593-019-0455-7

PMID: 31358992

Abstract

Animals

C9orf72 Protein

DNA Repeat Expansion

Humans

Neurodegenerative Diseases

Protein Biosynthesis

Ribosomal Proteins

ribosomal protein subunit 25

ribosome protein

unclassified drug

C9orf72 protein, human

guanine nucleotide exchange C9orf72

repetitive DNA

ribosome protein

RPS25 protein, human

amyotrophic lateral sclerosis

animal cell

Article

C9orf72 gene

cell fractionation

cell lysate

cell survival

controlled study

enzyme linked immunosorbent assay

frontotemporal dementia

gene

gene targeting

genetic screening

human

human cell

immunoblotting

immunocytochemistry

nonhuman

nuclear reprogramming

nucleotide repeat

priority journal

protein function

quantitative analysis

reverse transcription polymerase chain reaction

RNA translation

sequence analysis

animal

degenerative disease

genetics

protein synthesis

Nucleotide repeat expansions in the C9orf72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. Unconventional translation (RAN translation) of C9orf72 repeats generates dipeptide repeat proteins that can cause neurodegeneration. We performed a genetic screen for regulators of RAN translation and identified small ribosomal protein subunit 25 (RPS25), presenting a potential therapeutic target for C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia and other neurodegenerative diseases caused by nucleotide repeat expansions. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

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Title: RPS25 is required for efficient RAN translation of C9orf72 and other neurodegenerative disease-associated nucleotide repeats
Creators: S.B. Yamada - Stanford University
T.F. Gendron - Mayo Clinic in Florida
T. Niccoli - UK Dementia Research Institute
N.R. Genuth - Stanford University
R. Grosely - Stanford University
Y. Shi - University of Southern California
I. Glaria - University College London
N.J. Kramer - Stanford University
L. Nakayama - Stanford University
S. Fang - Stanford University
T.J.I. Dinger - Stanford University
A. Thoeng - University College London
G. Rocha - Broad Center
M. Barna - Stanford University
J.D. Puglisi - Stanford University
L. Partridge - University College London
J.K. Ichida - University of Southern California
A.M. Isaacs - UK Dementia Research Institute
L. Petrucelli - Mayo Clinic in Florida
A.D. Gitler - Stanford University
Publication Details: Nature Neuroscience, Vol.22(9), pp.1383-1388
Publisher: Nature Publishing Group; NEW YORK
Number of pages: 9
Grant note: National Institutes of Health (NIH): R35NS097263, AI099506, AG064690, R35NS097273, P01NS099114, R01NS097850 Target ALSUS Department of DefenseMuscular Dystrophy Association: 2T32HG000044-21 NIHGRI Brain Rejuvenation Project of the Wu Tsai Neurosciences InstituteEuropean Research Council: ERC-2014-CoG-648716 Alzheimer's Research UKMedical Research CouncilRobert Packard Center for ALS Research at Johns HopkinsMedical Research Council: UKDRI-1006 Motor Neurone Disease Association: Isaacs/Apr13/818-791, Isaacs/Apr15/834-791 MRC: UKDRI-1006 Eunice Kennedy Shriver National Institute of Child Health and Human Development: R01HD086634 National Human Genome Research Institute: T32HG000044 National Institute of Neurological Disorders and Stroke: P01NS099114, R35NS097273, R35NS097263 National Institute on Aging; National Institute of Neurological Disorders and Stroke: R01NS097850
This work was supported by National Institutes of Health (NIH) grants nos. R35NS097263 (A.D.G.), AI099506 (J.D.P), AG064690 (A.D.G. and J.D.P.), R35NS097273 (L.P.), P01NS099114 (T.F.G., L.P) and R01NS097850 (J.K.I.), the Robert Packard Center for ALS Research at Johns Hopkins (L.P., A.D.G.), Target ALS (L.P., A.D.G., T.F.G.), the US Department of Defense (J.D.P., A.D.G., J.K.I.), the Muscular Dystrophy Association (J.K.I.), 2T32HG000044-21 NIHGRI training grant (S.B.Y.), the Brain Rejuvenation Project of the Wu Tsai Neurosciences Institute (A.D.G.), the European Research Council grant no. ERC-2014-CoG-648716 (A.M.I.), Alzheimer's Research UK (A.M.I.) and the Medical Research Council (A.M.I.). J.K.I. is supported by funding for a New York Stem Cell Foundation-Robertson Investigatorship. We thank Dr. L. Ranum (University of Florida) for sharing the huntingtin poly(alanine) antibody. We thank M. Bassik for the HeLa Cas9-BFP cell lines. We thank H. Tricoire (French National Center for Scientific Research) for the generous gift of the original elavGS 301.2 line.
Comment: Export Date: 27 February 2026; Cited By: 76; CODEN: NANEF
Academic Unit: Level 02 - Executives; Executives; UMMG Department of Neurology
Resource Type: Journal article
PMID: 31358992
Record Identifier: 991032996192402976