GavaghanCommunications | Science for scientists. Issue 3, 23 - 29.8.10

Item 1: Keywords.
ALS, Ataxin-2,
TDP-43, RNA.

Ataxin-2 protein interaction with TDP-43 hints at an RNA related role as part of complex pathogenesis in ALS.

Of 40 genes found to enhance or suppress TDP-43 activity in yeast strains one shares a common evolutionary ancestry with ataxin-2 found in humans. The yeast homologue of human ataxin-2 enhanced and did not suppress the toxicity of TDP-43. The homologue did not enhance the toxicity of alpha-synuclein or mutant huntingtin fragment.

Mutant TDP-43 expressed in the eyes of drosophilia, their nervous system and motor neurones were associated with, respectively, progressive degeneration of eye structure, reduced life span when expressed in the nervous system and loss of motility.

Because of the effect of ataxin-2 homologues found on yeast and drosophilia the group investigated whether the ataxin-2 homologues in yeast and ataxin-2 could physically associate with TDP-43 protein within respectively yeast and human cells. Working with fluorescent protein tagging, immunoprecipitation and fluorescence micrsoscopy the ataxin-2 and TDP-43 were shown to exist in physical association.

Next the group mutated the residues in RNA recognition motifs (RRM) and observed a suppression of ataxin-2 and TDP-43 physical association, and also observed that RRM mutations completely eliminated TDP-43 toxicity in yeast. The observed association of TDP-43 and ataxin-2 in the cytoplasm might be transient.

Correction for clarification - the RRM is on TDP-43.

The ataxin-2 aggregation in the spinal cord neurons of 6 ALS patients was 27 per cent compared with 5 per cent in control neurons.

Data showed an association with ALS of 27 to 33 glutamine expansions in ataxin-2.

No physical association was observed of either normal or expanded ataxin-2 and endogenous TDP-43, though functional commonality of significnce to ALS pathogenisis was observed for the two proteins under stress conditions.

Item based on a paper published in Nature developed from material embargoed for 26.8.10: Ataxin-2 intermediate-lenghth polyglutamine expansions are associated with increased risk for ALS. Authors: Andrew C. Elden et al. DOI:10:1038/nature09320.

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