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

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

Authors

Ana Jovičić¹, Jerome Mertens², Steven Boeynaems^{3

4}, Elke Bogaert^{3

4}, Noori Chai^{1

5}, Shizuka B Yamada^{1

6}, Joseph W Paul 3rd¹, Shuying Sun⁷, Joseph R Herdy², Gregor Bieri^{1

5}, Nicholas J Kramer^{1

5}, Fred H Gage², Ludo Van Den Bosch^{3

4}, Wim Robberecht^{3

4

8}, Aaron D Gitler¹

Affiliations

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.

PMID: 26308983
PMCID: PMC4552077
DOI: 10.1038/nn.4085

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Active Transport, Cell Nucleus / physiology
Amyotrophic Lateral Sclerosis / genetics
Amyotrophic Lateral Sclerosis / metabolism*
Animals
C9orf72 Protein
Cell Nucleus / genetics
Cell Nucleus / metabolism*
Cells, Cultured
DNA Repeat Expansion / physiology*
Dipeptides / genetics
Dipeptides / metabolism*
Frontotemporal Dementia / genetics
Frontotemporal Dementia / metabolism*
Gene Deletion
Humans
Mice
Proteins / genetics
Proteins / metabolism*
Yeasts

Substances

C9orf72 Protein
C9orf72 protein, human
Dipeptides
Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding