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Arfaptin 2 regulates the aggregation of mutant huntingtin protein.

Research paper by Peter J PJ Peters, Ke K Ning, Felipe F Palacios, Rita L RL Boshans, Aleksey A Kazantsev, Leslie M LM Thompson, Ben B Woodman, Gillian P GP Bates, Crislyn C D'Souza-Schorey

Indexed on: 21 Feb '02Published on: 21 Feb '02Published in: Nature Cell Biology



Abstract

Huntington's disease (HD) is an inherited neurodegenerative disorder. Here we demonstrate that expression of arfaptin 2/POR1 (partner of Rac1) in cultured cells induces the formation of pericentriolar and nuclear aggregates, which morphologically resemble mutant huntingtin aggregates characteristic of HD. Endogenous arfaptin 2 localizes to aggregates induced by expression of an abnormal amino-terminal fragment of huntingtin that contains polyglutamine (polyQ) expansions. A dominant inhibitory mutant of arfaptin 2 inhibits aggregation of mutant huntingtin, but not in the presence of proteasome inhibitors. Using cell-free biochemical assays, we show that arfaptin 2 inhibits proteasome activity. Finally, we show that expression of arfaptin 2 is increased at sites of neurodegeneration and the protein localizes to huntingtin aggregates in HD transgenic mouse brains. Our data suggest that arfaptin 2 is involved in regulating huntingtin protein aggregation, possibly by impairing proteasome function.