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Sci Rep. 2016 Feb 12;6:20877. doi: 10.1038/srep20877.

Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD.

Author information

1
KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), B-3000 Leuven, Belgium.
2
VIB, Vesalius Research Center, Laboratory of Neurobiology, B-3000 Leuven, Belgium.
3
Department of Molecular Genetics, VIB, B-2610 Antwerp, Belgium.
4
Institute Born-Bunge, University of Antwerp, B-2610 Antwerp, Belgium.
5
Department of Neurology, University Hospital Ghent and University of Ghent, B-9000 Ghent, Belgium.
6
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305 USA.
7
Switch Laboratory, VIB, B-3000 Leuven, Belgium.
8
Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium.
9
VIB Laboratory of Systems Biology, Gaston Geenslaan 1, B-3001 Leuven, Belgium.
10
KU Leuven - University of Leuven, Department of Microbial and Molecular Systems, Laboratory for Genetics and Genomics, Gaston Geenslaan 1, B-3001 Leuven, Belgium.
11
KU Leuven - University of Leuven, Department of Human Genetics, Laboratory of Behavioral and Developmental Genetics, B-3000 Leuven, Belgium.
12
VIB Center for the Biology of Disease, B-3000 Leuven, Belgium.
13
University Hospitals Leuven, Department of Neurology, B-3000 Leuven, Belgium.

Abstract

Hexanucleotide repeat expansions in C9orf72 are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) (c9ALS/FTD). Unconventional translation of these repeats produces dipeptide repeat proteins (DPRs) that may cause neurodegeneration. We performed a modifier screen in Drosophila and discovered a critical role for importins and exportins, Ran-GTP cycle regulators, nuclear pore components, and arginine methylases in mediating DPR toxicity. These findings provide evidence for an important role for nucleocytoplasmic transport in the pathogenic mechanism of c9ALS/FTD.

PMID:
26869068
PMCID:
PMC4751451
DOI:
10.1038/srep20877
[Indexed for MEDLINE]
Free PMC Article

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