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.
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Acknowledgements
We thank E. Signer, and J. Schweitzer for discussions and critical reading of the manuscript. We thank J. Exton for arfaptin 2 cDNA, J. Dorsman for huntingtin antibodies, E. Van Donselaar and Erik Bos for excellent technical assistance with EM procedures, A. Mahal for genotyping the mice, O. Spasic-Boscovic for assistance with immunocytochemistry and B. Apostal for assistance with generating the cell line expressing GFP–HttexpolyQ. We acknowledge the EM division of Utrecht University for excellent technical assistance with photography and handling of EM micrographs. This work was supported in part by grants from the Hereditary Diseases Foundation, Cure HD Initiative, to C.D.-S and L.T., and by grants from the Human Science Frontiers Program and the Wellcome Trust to G.B.
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Cytoplasmic distribution of arfaptin 2. (PDF 1310 kb)
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Peters, P., Ning, K., Palacios, F. et al. Arfaptin 2 regulates the aggregation of mutant huntingtin protein. Nat Cell Biol 4, 240–245 (2002). https://doi.org/10.1038/ncb761
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DOI: https://doi.org/10.1038/ncb761
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