Chapter

Perturbed RNA metabolism in amyotrophic lateral sclerosis

Kathryn Volkening and Michael J. Strong

in Amyotrophic Lateral Sclerosis and the Frontotemporal Dementias

Published on behalf of Oxford University Press

Published in print October 2012 | ISBN: 9780199590674
Published online November 2012 | e-ISBN: 9780191753466 | DOI: http://dx.doi.org/10.1093/med/9780199590674.003.0022
Perturbed RNA metabolism in amyotrophic lateral sclerosis

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The discovery of the involvement of the RNA-binding proteins transactive response DNA-binding protein of 43 kDa (TDP-43) and FUS/TLS in ALS has given rise to the possibility that ALS is a disorder of RNA metabolism. Before these discoveries, it was known that ALS affected motor neurones have a selective decrease in polyadenylated mRNA and low molecular weight neurofilament (NFL) mRNA levels while sparing those of medium molecular weight neurofilament (NFM) and high molecular weight neurofilament (NFH). That this selective NF stoichiometry alteration is of pathological relevance to ALS is supported by murine models in which NF stoichiometry was disrupted by either overexpressing NFH or knocking out or disrupting NFL expression and produce neuronal NF aggregates similar to those found in ALS. The presence of NF aggregates predisposes neurones to risk of oxidative stress, excitotoxicity, and cell death. To understand the isolated reductions of NFL mRNA in ALS, we have focused on defining the complex of proteins that regulate NFL mRNA stability and how these differ between ALS and healthy control tissues.

Chapter.  6273 words.  Illustrated.

Subjects: Neurology

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