Journal
MOLECULAR AND CELLULAR NEUROSCIENCE
Volume 56, Issue -, Pages 475-486Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.mcn.2013.03.006
Keywords
ALS; FET family; FTLD; FUS; Neurodegeneration; Nuclear import; Stress granules; TLS; Transportin
Categories
Funding
- Competence Network for Neurodegenerative Diseases (KNDD) of the Bundesministerium far Bildung und Forschung (BMBF)
- Consortium of Centers of Excellence in Neurodegenerative Brain Diseases (CoEN)
- European Research Council under the European Union's Seventh Framework Programme/ERC [321366]
- Robert Bosch Foundation
- European Research Council (ERC) [321366] Funding Source: European Research Council (ERC)
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Fused in sarcoma (FUS) is a nuclear DNA/RNA binding protein that regulates different steps of gene expression, including transcription, splicing and mRNA transport. FUS has been implicated in neurodegeneration, since mutations in FUS cause familial amyotrophic lateral sclerosis (ALS-FUS) and lead to the cytosolic deposition of PUS in the brain and spinal cord of ALS-FUS patients. moreover, PUS and two related proteins of the same protein family (FET family) are co-deposited in cytoplasmic inclusions in a subset of patients with frontotemporal lobar degeneration (FTLD-FUS). Cytosolic deposition of these otherwise nuclear proteins most likely causes the loss of a yet unknown essential nuclear function and/or the gain of a toxic function in the cytosol. Here we summarize what is known about the physiological functions of the FET proteins in the nucleus and cytoplasm and review the distinctive pathomechanisms that lead to the deposition of only FUS in ALS-FUS, but all three FET proteins in FTLD-FUS. We suggest that ALS-FUS is caused by a selective dysfunction of PUS, while FTLD-FUS may be caused by a dysfunction of the entire FET family. This article is part of a Special Issue entitled 'RNA and splicing regulation in neurodegeneration'. (C) 2013 Elsevier Inc. All rights reserved.
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