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Trends Neurosci. 2011 Jul;34(7):339-48. doi: 10.1016/j.tins.2011.05.002. Epub 2011 Jun 22.

TDP-43 and FUS: a nuclear affair.

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1
Adolf-Butenandt-Institute, Biochemistry, Ludwig-Maximilians-University and German Center for Neurodegenerative Diseases (DZNE) Munich, Schillerstr. 44, 80336 Munich, Germany.

Abstract

Misfolded TAR DNA binding protein 43 (TDP-43) and Fused-In-Sarcoma (FUS) protein have recently been identified as pathological hallmarks of the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) characterized by the presence of ubiquitin-positive inclusions (FTLD-U). Although TDP-43 and FUS are normally located predominantly in the nucleus, pathological TDP-43 and FUS inclusions are mostly found in the cytosol. Cytosolic deposition is paralleled by a striking nuclear depletion of either protein. Based on a number of recent findings, we postulate that defects in nuclear import are an important step towards TDP-43 and FUS dysfunction. Failure of nuclear transport can arise from mutations within a nuclear localization signal or from age-related decline of nuclear import mechanisms. We propose that nuclear import defects in combination with additional hits, for example cellular stress and genetic risk factors, may be a central underlying cause of ALS and FTLD-U pathology.

PMID:
21700347
DOI:
10.1016/j.tins.2011.05.002
[Indexed for MEDLINE]

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