Dominant-negative effect of mutant valosin-containing protein in aggresome formation

Makiko-Iijima Kitami, Toshiaki Kitami, Masami Nagahama, Mitsuo Tagaya, Seiji Hori, Akira Kakizuka, Yoshikuni Mizuno, Nobutaka Hattori
FEBS Letters 2006 January 23, 580 (2): 474-8
Lewy bodies (LBs) are the pathologic hallmark of Parkinson's disease. Recent studies revealed that LBs exhibit several morphologic and molecular similarities to aggresomes. Aggresomes are perinuclear aggregates representing intracellular deposits of misfolded proteins. Recently, valosin-containing protein (VCP) was one of the components of LBs, suggesting its involvement in LB formation. Here, we showed the localization of VCP in aggresomes induced by a proteasome inhibitor in cultured cells. Cells overexpressing mutant VCP (K524M: D2) showed reduced aggresome formation relative to those overexpressing wild-type and mutant (K251M: D1) VCPs. Our findings suggest that the D2 domain is involved in aggresome formation.

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