Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72

Q. Zhu; J. Jiang; T.F. Gendron; M. McAlonis-Downes; L. Jiang; A. Taylor; S. Diaz Garcia; S. Ghosh Dastidar; M.J. Rodriguez; P. King; Y. Zhang; A.R. La Spada; H. Xu; L. Petrucelli; J. Ravits; S. Da Cruz; C. Lagier-Tourenne; D.W. Cleveland

doi:10.1038/s41593-020-0619-5

Journal article

Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72

Q. Zhu, J. Jiang, T.F. Gendron, M. McAlonis-Downes, L. Jiang, A. Taylor, S. Diaz Garcia, S. Ghosh Dastidar, M.J. Rodriguez, P. King, …

Nature Neuroscience, Vol.23(5), pp.615-624

2020

DOI: https://doi.org/10.1038/s41593-020-0619-5

PMID: 32284607

Abstract

Amyotrophic Lateral Sclerosis

Animals

C9orf72 Protein

DNA Repeat Expansion

Female

Frontotemporal Dementia

Male

Mice

Mice, Inbred C57BL

Mice, Transgenic

autophagy related protein

guanine nucleotide exchange C9orf72

LC3B I protein

LC3B II protein

RNA

sequestosome 1

unclassified drug

guanine nucleotide exchange C9orf72

repetitive DNA

adult

age

allele

amyotrophic lateral sclerosis

animal cell

animal experiment

animal tissue

Article

autophagy (cellular)

C9orf72 gene

cell activation

cell loss

cognitive defect

controlled study

death

disease exacerbation

embryo

frontotemporal dementia

gain of toxicity

gene expression

gene structure

genotype

glia cell

human

human tissue

learning disorder

motor dysfunction

mouse

nerve cell

nonhuman

priority journal

protein degradation

protein function

repeat expansion

RNA translation

splenomegaly

toxicological parameters

ubiquitination

amyotrophic lateral sclerosis

animal

C57BL mouse

female

frontotemporal dementia

genetics

male

metabolism

pathology

transgenic mouse

Hexanucleotide expansions in C9orf72, which encodes a predicted guanine exchange factor, are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although repeat expansion has been established to generate toxic products, mRNAs encoding the C9ORF72 protein are also reduced in affected individuals. In this study, we tested how C9ORF72 protein levels affected repeat-mediated toxicity. In somatic transgenic mice expressing 66 GGGGCC repeats, inactivation of one or both endogenous C9orf72 alleles provoked or accelerated, respectively, early death. In mice expressing a C9orf72 transgene with 450 repeats that did not encode the C9ORF72 protein, inactivation of one or both endogenous C9orf72 alleles exacerbated cognitive deficits, hippocampal neuron loss, glial activation and accumulation of dipeptide-repeat proteins from translation of repeat-containing RNAs. Reduced C9ORF72 was shown to suppress repeat-mediated elevation in autophagy. These efforts support a disease mechanism in ALS/FTD resulting from reduced C9ORF72, which can lead to autophagy deficits, synergizing with repeat-dependent gain of toxicity. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

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Title: Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72
Creators: Q. Zhu - Ludwig Cancer Research
J. Jiang - Emory University
T.F. Gendron - Mayo Clinic in Florida
M. McAlonis-Downes - Ludwig Cancer Research
L. Jiang - Sanford Burnham Prebys Medical Discovery Institute
A. Taylor - University of California San Diego
S. Diaz Garcia
S. Ghosh Dastidar
M.J. Rodriguez
P. King - Ludwig Cancer Research
Y. Zhang - Mayo Clinic in Florida
A.R. La Spada - Duke University
H. Xu - Discovery Institute
L. Petrucelli - Mayo Clinic in Florida
J. Ravits - University of California San Diego
S. Da Cruz - Ludwig Cancer Research
C. Lagier-Tourenne - Massachusetts General Hospital
D.W. Cleveland - University of California San Diego
Publication Details: Nature Neuroscience, Vol.23(5), pp.615-624
Publisher: Nature Research; BERLIN
Number of pages: 15
Grant note: NINDS/NIH: R35-NS097273, P01-NS084974, R01-NS088689, R01-NS27036, R01-NS087227 NIA/NIH: P50-AG005131 Target ALSHealey Family ALS Endowed Chair for ResearchMilton Safenowitz Postdoctoral FellowshipSTARTER grant from the ALS AssociationMuscular Dystrophy Association: 479769 National Institute of Neurological Disorders and Stroke: R35NS097273, P01NS099114 National Institute on Aging: P01NS084974, P30AG062429 National Institute on Aging; National Institute of Neurological Disorders and Stroke: R01NS027036
We thank B. Myers, M. Maldonado, J. Kim, J. Lim, J. Yasis, C.J. Heyser, D. Ditsworth, K. Osborn and J. Chew for their advice and technical assistance. We thank M. Fugere and B. Kaspar at AveXis for providing help in sorting mouse ESC-derived motor neurons. We thank Ionis Pharmaceuticals for providing ASOs. We thank all members of the D.W.C., C.L.-T., J.R., and S.D.C. groups for critical suggestions on this project. This work was supported by grants from NINDS/NIH R01-NS27036 to D.W.C. and S.D.C. and R01-NS087227 to C.L.-T.; from the NIA/NIH-supported UCSD Alzheimer's Disease Research Center (P50-AG005131) to C.L.-T. and D.W.C.; from Target ALS to C.L.-T. and J.R.; from NINDS/NIH R35-NS097273, P01-NS084974 and R01-NS088689 to L.P.; from P01-NS099114 to T.G. and L.P.; and from Target ALS to T.G., L.P. and Y.Z. C.L.-T. is the recipient of the Healey Family ALS Endowed Chair for Research. Q.Z. was the recipient of a Milton Safenowitz Postdoctoral Fellowship and a STARTER grant from the ALS Association. J.J. was the recipient of a career development grant from the Muscular Dystrophy Association (479769).
Comment: Export Date: 27 February 2026; Cited By: 183; CODEN: NANEF
Academic Unit: Level 02 - Executives; Executives; UMMG Department of Neurology
Resource Type: Journal article
PMID: 32284607
Record Identifier: 991032995743102976