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Nat Neurosci. 2016 May;19(5):668-677. doi: 10.1038/nn.4272. Epub 2016 Mar 21.

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

Author information

1
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
2
Department of Neurology, School of Medicine, Johns Hopkins University, Maryland, USA.
3
Brain Science Institute, School of Medicine, Johns Hopkins University, Maryland, USA.
4
Department of Neuroscience, School of Medicine, Johns Hopkins University, Maryland, USA.
5
Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
6
Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida, USA.
7
Ludwig Institute, University of California at San Diego, La Jolla, California, USA.
8
Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
9
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
10
Institute for Metabolic Biochemistry, Ludwig Maximilians University Munich, Munich, Germany.
11
Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
12
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, USA.
13
Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
14
Integrative Physiology, Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, USA.

Abstract

Neuronal inclusions of poly(GA), a protein unconventionally translated from G4C2 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.

PMID:
26998601
PMCID:
PMC5138863
DOI:
10.1038/nn.4272
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no competing financial interests.

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