期刊
EMBO JOURNAL
卷 31, 期 22, 页码 4258-4275出版社
WILEY
DOI: 10.1038/emboj.2012.261
关键词
frontotemporal lobar degeneration (FTLD); fused in sarcoma (FUS); Transportin (TRN)
资金
- Sonderforschungsbereich Molecular Mechanisms of Neurodegeneration [SFB 596]
- Competence Network for Neurodegenerative Diseases (KNDD) of the Bundesministerium fur Bildung und Forschung (BMBF)
- Swiss National Science Foundation [31003A-132864]
- Robert Bosch Foundation
- Austrian Academy of Sciences
- Bavarian Ministry of Sciences, Research and the Arts in the framework of the Bavarian Molecular Biosystems Research Network
- German Research Foundation (DFG) [MA 5703/1-1]
- Elite Network of Bavaria
- NIHR Oxford Biomedical Research Centre
- Canadian Institutes of Health Research [179009, 74580]
- Pacific Alzheimer's Research Foundation centre [C06-01]
- 'Forschungsprofessur' of the Ludwig-Maximilians University
- Swiss National Science Foundation (SNF) [31003A_132864] Funding Source: Swiss National Science Foundation (SNF)
- Parkinson's UK [J-0901] Funding Source: researchfish
Fused in sarcoma (FUS) is a nuclear protein that carries a proline-tyrosine nuclear localization signal (PY-NLS) and is imported into the nucleus via Transportin (TRN). Defects in nuclear import of FUS have been implicated in neurodegeneration, since mutations in the PY-NLS of FUS cause amyotrophic lateral sclerosis (ALS). Moreover, FUS is deposited in the cytosol in a subset of frontotemporal lobar degeneration (FTLD) patients. Here, we show that arginine methylation modulates nuclear import of FUS via a novel TRN-binding epitope. Chemical or genetic inhibition of arginine methylation restores TRN-mediated nuclear import of ALS-associated FUS mutants. The unmethylated arginine-glycine-glycine domain preceding the PY-NLS interacts with TRN and arginine methylation in this domain reduces TRN binding. Inclusions in ALS-FUS patients contain methylated FUS, while inclusions in FTLD-FUS patients are not methylated. Together with recent findings that FUS co-aggregates with two related proteins of the FET family and TRN in FTLD-FUS but not in ALS-FUS, our study provides evidence that these two diseases may be initiated by distinct pathomechanisms and implicates alterations in arginine methylation in pathogenesis. The EMBO Journal (2012) 31, 4258-4275. doi:10.1038/emboj.2012.261; Published online 11 September 2012
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