Journal
TRENDS IN NEUROSCIENCES
Volume 34, Issue 7, Pages 339-348Publisher
ELSEVIER SCIENCE LONDON
DOI: 10.1016/j.tins.2011.05.002
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Funding
- Center for Integrated Protein Science Munich (CIPSM)
- Competence Network of Neurodegenerative Diseases (KNDD) of the Bundesministerium fur Bildung und Forschung (BMBF)
- Sonderforschungsbereich Molecular Mechanisms of Neurodegeneration [SFB 596]
- EMBO
- Ludwig-Maximilians University
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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.
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