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Nat Neurosci. 2015 Sep;18(9):1226-9. doi: 10.1038/nn.4085.

Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS.

Author information

1
Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
2
Salk Institute for Biological Studies, Sanford Consortium for Regenerative Medicine, La Jolla, California, USA.
3
KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), Leuven, Belgium.
4
Vlaams Instituut voor Biotechnologie (VIB), Vesalius Research Center, Laboratory of Neurobiology, Leuven, Belgium.
5
Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, California, USA.
6
Department of Biology, Stanford University, Stanford, California, USA.
7
Ludwig Institute for Cancer Research, Departments of Cellular and Molecular Medicine and of Neurosciences, University of California at San Diego, La Jolla, California, USA.
8
University Hospitals Leuven, Department of Neurology, Leuven, Belgium.

Abstract

C9orf72 mutations are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dipeptide repeat proteins (DPRs) produced by unconventional translation of the C9orf72 repeat expansions cause neurodegeneration in cell culture and in animal models. We performed two unbiased screens in Saccharomyces cerevisiae and identified potent modifiers of DPR toxicity, including karyopherins and effectors of Ran-mediated nucleocytoplasmic transport, providing insight into potential disease mechanisms and therapeutic targets.

PMID:
26308983
PMCID:
PMC4552077
DOI:
10.1038/nn.4085
[Indexed for MEDLINE]
Free PMC Article
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