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Review
. 2011 Dec;21(6):904-19.
doi: 10.1016/j.conb.2011.05.029. Epub 2011 Aug 2.

Understanding the role of TDP-43 and FUS/TLS in ALS and beyond

Sandrine Da Cruz  1 , Don W Cleveland
Affiliations
Review

Understanding the role of TDP-43 and FUS/TLS in ALS and beyond

Sandrine Da Cruz et al. Curr Opin Neurobiol. 2011 Dec.

Abstract

Dominant mutations in two DNA/RNA binding proteins, TDP-43 and FUS/TLS, are causes of inherited Amyotrophic Lateral Sclerosis (ALS). TDP-43 and FUS/TLS have striking structural and functional similarities, implicating alterations in RNA processing as central in ALS. TDP-43 has binding sites within a third of all mouse and human mRNAs in brain and this binding influences the levels and splicing patterns of at least 20% of those mRNAs. Disease modeling in rodents of the first known cause of inherited ALS-mutation in the ubiquitously expressed superoxide dismutase (SOD1)-has yielded non-cell autonomous fatal motor neuron disease caused by one or more toxic properties acquired by the mutant proteins. In contrast, initial disease modeling for TDP-43 and FUS/TLS has produced highly varied phenotypes. It remains unsettled whether TDP-43 and FUS/TLS mutants provoke disease from a loss of function or gain of toxicity or both. TDP-43 or FUS/TLS misaccumulation seems central not just to ALS (where it is found in almost all instances of disease), but more broadly in neurodegenerative disease, including frontal temporal lobular dementia (FTLD-U) and many examples of Alzheimer's or Huntington's disease.

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Figures

Figure 1
Figure 1. TDP-43 and FUS/TLS mutations in ALS and FTLD patients
(Upper panel) Forty-four mutations have been identified in TDP-43 in sporadic and familial ALS patients and in rare FTLD patients, with most lying in the C-terminal glycine-rich region. The putative prion domain comprises amino acids from 277–414. (Lower panel) Forty-three mutations have been identified in FUS/TLS in familial and sporadic ALS cases and in rare FTLD patients. Most mutations are clustered in the last 17 amino acids and in the glycine-rich region and the putative prion domain comprises amino acids 1–239.
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