Human Molecular Genetics Advance Access originally published online on August 22, 2005
Human Molecular Genetics 2005 14(19):2893-2909; doi:10.1093/hmg/ddi321
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Ataxin-2 and huntingtin interact with endophilin-A complexes to function in plastin-associated pathways
1Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany, 2Max Planck Institute for Informatics, Stuhlsatzenhausweg 85, 66123 Saarbrücken, Germany and 3Max Delbrueck Center for Molecular Medicine, Robert-Roessle-Strasse 10, 13092 Berlin, Germany
* To whom correspondence should be addressed. Tel: +49 3084131351; Fax: +49 3084131380; Email: krobitsc{at}molgen.mpg.de
Received July 6, 2005; Revised August 10, 2005; Accepted August 18, 2005
Spinocerebellar ataxia type 2 is an inherited neurodegenerative disorder that is caused by an expanded trinucleotide repeat in the SCA2 gene, encoding a polyglutamine stretch in the gene product ataxin-2. Although evidence has been provided that ataxin-2 is involved in RNA metabolism, the physiological function of ataxin-2 remains unclear. Here, we demonstrate that ataxin-2 interacts with two members of the endophilin family, endophilin-A1 and endophilin-A3. To elucidate the physiological implications of these interactions, we exploited yeast as a model system and discovered that expression of ataxin-2 as well as both endophilin proteins is toxic for yeast lacking the SAC6 gene product fimbrin, a protein involved in actin filament organization and endocytotic processes. Intriguingly, expression of huntingtin, another polyglutamine protein interacting with endophilin-A3, was also toxic in 
sac6 yeast. These effects can be suppressed by simultaneous expression of one of the two human fimbrin orthologs, L- or T-plastin. Moreover, we have discovered that ataxin-2 associates with L- and T-plastin and that overexpression of ataxin-2 leads to accumulation of T-plastin in mammalian cells. Thus, our findings suggest an interplay between ataxin-2, endophilin proteins and huntingtin in plastin-associated cellular pathways.
The authors wish to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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