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A New Player In Huntington's Disease?

  February, 18 2002 3:55
your information resource in human molecular genetics
Huntington's disease (HD) is an inherited degenerative brain disease which affects thousands of people in western countries and for which there is no effective cure or treatment available at present. HD is due to mutations of the ‘huntingtin’ gene. The corresponding mutant Huntingtin protein (Htt) is prone to aggregation. While formation of Htt aggregate correlates with HD pathogenesis, it is still unclear whether it is actually causal for neural loss.

In the March issue of Nature Cell Biology (article also published online), Crislyn D'Souza-Schorey and her colleagues at the University of Notre Dame in Illinois now show how Htt aggregation can be regulated by the arfaptin2 protein. Thus arfaptin-2 is a potentially important player in HD pathogenesis and represents a viable target for successful therapeutic intervention in the treatment of HD.

D'Souza-Schorey and colleagues show that expression of arfaptin in cultured cells induces the formation of aggregates containing the Htt protein and arfaptin2 proteins. Expression of the C terminal end of the protein had a similar effect as the full length protein. In contrast, expression of a truncated protein lacking the N terminal end, actually reduced Htt aggregation, so that could prove to be a valuable tool in clinical research. The authors also found increased arfaptin levels in the brain of a mouse model of HD as compared to the brain of healthy mice. And arfaptin2 localizes to Htt aggregates in diseased brains.

So how does arfaptin2 regulate Htt aggregation? Arfaptin2 was previously shown to regulate cytoskeletal remodelling, but the evidence so far is that arfaptin's affects on Htt aggregation is independent on its effects on the cytoskeleton. The authors have further data that are consistent with a different model: arfaptin2 would control the balance between Htt aggregation and its degradation, by direct inhibition of the proteasome.

In any case, this new link between arfaptin2 and Htt opens exciting new therapeutical strategies to combat HD, which now need to be explored in vivo.

Author contact:

Dr Crislyn D'Souza-Schorey
Department of Biological Sciences
University of Notre Dame
Notre Dame, IN, USA
Tel: +1 219 631 3735
E-mail: D'Souza-Schorey.1@nd.edu

(C) Nature Cell Biology press release.

Message posted by: Trevor M. D'Souza

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