C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins

Y.-J. Zhang; T.F. Gendron; J.C. Grima; H. Sasaguri; K. Jansen-West; Y.-F. Xu; R.B. Katzman; J. Gass; M.E. Murray; M. Shinohara; W.-L. Lin; A. Garrett; J.N. Stankowski; L. Daughrity; J. Tong; E.A. Perkerson; M. Yue; J. Chew; M. Castanedes-Casey; A. Kurti; Z.S. Wang; A.M. Liesinger; J.D. Baker; J. Jiang; C. Lagier-Tourenne; D. Edbauer; D.W. Cleveland; R. Rademakers; K.B. Boylan; G. Bu; C.D. Link; C.A. Dickey; J.D. Rothstein; D.W. Dickson; J.D. Fryer; L. Petrucelli

doi:10.1038/nn.4272

Journal article

C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins

Y.-J. Zhang, T.F. Gendron, J.C. Grima, H. Sasaguri, K. Jansen-West, Y.-F. Xu, R.B. Katzman, J. Gass, M.E. Murray, M. Shinohara, …

Nature Neuroscience, Vol.19(5), pp.668-677

2016

DOI: https://doi.org/10.1038/nn.4272

PMID: 26998601

Abstract

Amyotrophic Lateral Sclerosis

Animals

Atrophy

Behavior, Animal

Brain

Carrier Proteins

DNA-Binding Proteins

Frontotemporal Dementia

Gene Expression

Guanine Nucleotide Exchange Factors

Humans

Inclusion Bodies

Mice

Mutation

Nerve Degeneration

Neurons

Primary Cell Culture

Proteins

Ubiquitinated Proteins

HR23 protein

nucleocytoplasmic transport protein

poly(GA) protein

ubiquitinated protein

unclassified drug

xeroderma pigmentosum group C protein

C9orf72 protein, mouse

carrier protein

DNA binding protein

guanine nucleotide exchange factor

poly(glycyl-alanyl)

protein

Rad23a protein, mouse

Rad23b protein, mouse

TDP-43 protein, mouse

ubiquitinated protein

Xpc protein, mouse

amyotrophic lateral sclerosis

animal experiment

animal model

Article

C9ORF72 gene

frontotemporal dementia

gene

mouse

nerve degeneration

neuropathology

neurotoxicity

nonhuman

nucleocytoplasmic transport

phenotype

priority journal

protein aggregation

protein defect

TDP 43 proteinopathy

animal

animal behavior

atrophy

brain

cell inclusion

gene expression

genetics

human

metabolism

mutation

nerve cell

pathology

primary cell culture

ultrastructure

Neuronal inclusions of poly(GA), a protein unconventionally translated from G 4 C 2 repeat expansions in C9ORF72, are abundant in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by this mutation. To investigate poly(GA) toxicity, we generated mice that exhibit poly(GA) pathology, neurodegeneration and behavioral abnormalities reminiscent of FTD and ALS. These phenotypes occurred in the absence of TDP-43 pathology and required poly(GA) aggregation. HR23 proteins involved in proteasomal degradation and proteins involved in nucleocytoplasmic transport were sequestered by poly(GA) in these mice. HR23A and HR23B similarly colocalized to poly(GA) inclusions in C9ORF72 expansion carriers. Sequestration was accompanied by an accumulation of ubiquitinated proteins and decreased xeroderma pigmentosum C (XPC) levels in mice, indicative of HR23A and HR23B dysfunction. Restoring HR23B levels attenuated poly(GA) aggregation and rescued poly(GA)-induced toxicity in neuronal cultures. These data demonstrate that sequestration and impairment of nuclear HR23 and nucleocytoplasmic transport proteins is an outcome of, and a contributor to, poly(GA) pathology. © 2016 Nature America, Inc. All rights reserved.

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Title: C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins
Creators: Y.-J. Zhang - Mayo Clinic in Florida
T.F. Gendron - Mayo Clinic in Florida
J.C. Grima - Johns Hopkins Medicine
H. Sasaguri - Jacksonville College
K. Jansen-West - Mayo Clinic in Florida
Y.-F. Xu - Mayo Clinic in Florida
R.B. Katzman - Jacksonville College
J. Gass - Mayo Clinic in Florida
M.E. Murray - Mayo Clinic in Florida
M. Shinohara - Mayo Clinic in Florida
W.-L. Lin - Mayo Clinic in Florida
A. Garrett - Mayo Clinic in Florida
J.N. Stankowski - Jacksonville College
L. Daughrity - Mayo Clinic in Florida
J. Tong - Mayo Clinic in Florida
E.A. Perkerson - Mayo Clinic in Florida
M. Yue - Mayo Clinic in Florida
J. Chew - Jacksonville College
M. Castanedes-Casey - Mayo Clinic in Florida
A. Kurti - Mayo Clinic in Florida
Z.S. Wang - Jacksonville College
A.M. Liesinger - Jacksonville College
J.D. Baker - University of South Florida
J. Jiang
C. Lagier-Tourenne - Massachusetts General Hospital
D. Edbauer - German Center for Neurodegenerative Diseases
D.W. Cleveland - University of California San Diego
R. Rademakers - Jacksonville College
K.B. Boylan - Mayo Clinic in Florida
G. Bu - Mayo Clinic in Florida
C.D. Link - University of Colorado Boulder
C.A. Dickey - University of South Florida
J.D. Rothstein - Johns Hopkins University
D.W. Dickson - Mayo Clinic in Florida
J.D. Fryer - Mayo Clinic
L. Petrucelli - Mayo Clinic in Florida
Publication Details: Nature Neuroscience, Vol.19(5), pp.668-677
Publisher: Nature Publishing Group; NEW YORK
Number of pages: 14
Grant note: US National Institutes of Health (NIH) National Institute on Aging: R01AG026251 NIH National Institute of Neurological Disorders and Stroke: R21NS079807, R21NS089979, F32NS087842, R01NS080882, R01NS085207, U54NS091046, R01NS063964, R01NS077402, R21NS084528, P01NS084974, R01NS088689 National Institute of Environmental Health Services: R01ES20395 Department of Defense (ALSRP): AL130125 Mayo Clinic FoundationMayo Clinic Center for Individualized MedicineAlzheimer's Association: NIRP-14-304425, NIRP-12-259289 Amyotrophic Lateral Sclerosis AssociationRobert Packard Center for ALS Research at Johns HopkinsTarget ALSBrain Science InstituteLudwig Institute for Cancer ResearchEuropean Union: 617198 National Science Foundation Graduate Research Fellowship AwardThomas Shortman Training Fund Graduate ScholarshipAxol Science ScholarshipNational Institute on Aging: P01NS084974
We are grateful to all patients who agreed to donate post-mortem tissue. This work was supported by the US National Institutes of Health (NIH) National Institute on Aging (R01AG026251 (L.P.)); NIH National Institute of Neurological Disorders and Stroke (R21NS079807 (Y.-J.Z. and J.D.F.); R21NS089979 (T.F.G. and K.B.B.); F32NS087842 (J.J.); R01NS080882 (R.R.); R01NS085207 (J.D.R.); U54NS091046 (J.D.R.); R01NS063964 (L.P.); R01NS077402 (L.P.), R21NS084528 (L.P.); P01NS084974 (L.P., D.D., K.B.B. and R.R.); R01NS088689 (L.P.)); National Institute of Environmental Health Services (R01ES20395 (L.P.); Department of Defense (ALSRP AL130125 (L.P.)); Mayo Clinic Foundation (L.P.); Mayo Clinic Center for Individualized Medicine (L.P. and K.B.B.); Alzheimer's Association (NIRP-14-304425 (Y.-J.Z.); NIRP-12-259289 (J.D.F.)); Amyotrophic Lateral Sclerosis Association (Y.-J.Z., T.F.G., K.B.B., D.W.C. and L.P.); Robert Packard Center for ALS Research at Johns Hopkins (J.D.R. and L.P.), Target ALS (C.L.-T., J.D.R. and L.P.); Brain Science Institute (J.D.R.); the Ludwig Institute for Cancer Research (D.W.C. and C.L.T.), and the European Union's Seventh Framework Programme (FP7/2014-2019 grant 617198 (D.E.)). J.C.G. is the recipient of a National Science Foundation Graduate Research Fellowship Award, a Thomas Shortman Training Fund Graduate Scholarship and an Axol Science Scholarship.
Comment: Export Date: 27 February 2026; Cited By: 264; CODEN: NANEF
Academic Unit: Level 02 - Executives; Executives; UMMG Department of Neurology
Resource Type: Journal article
PMID: 26998601
Record Identifier: 991032995733402976