Conference Publication Details
Mandatory Fields
Toulouse A., Lager Gotaas I.
New Horizons in Medical Research
Alternative ribosomal translation as a pathological mechanism in polyglutamine neurological disorders.
2015
December
Published
1
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Optional Fields
University College Cork, Cork, Ireland
10-DEC-15
The polyglutamine disorders are a group of heterogeneous late-onset neurodegenerative disorders characterized by the expansion of a CAG trinucleotide repeat in the causative gene, the accumulation of insoluble protein material and premature neuronal cell death. Examples of these diseases include Huntington disease and the Spinocerebellar ataxias (SCAs). Recent work has provided support for several mechanisms that may account for neurodegeneration in these disorders but no unifying mechanism has emerged yet. We have previously demonstrated that in SCA3 the expanded CAG tract is prone to frameshifting that may lead to the production of polyalanine-containing proteins. In order to further document the occurrence of frameshifting, assess its role in cell toxicity and understand its mechanism, a cellular model was established. We show that this phenomenon results from ribosomal slippage towards the 1 frame leading to the production of polyalanine proteins. We also show that ribosomal frameshifting depends on the presence of long CAG tracts and that polyalanine frameshifted proteins are more toxic than their polyglutamine counterparts, possibly contributing to pathogenesis. Finally, we present evidence that ribosome-interacting drugs can modulate -1 frameshifting, representing a possible therapeutic target for these disorders.
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