Dominant-negative effect of mutant valosin-containing protein in aggresome formation.
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.
Kitami
Makiko-Iijima
MI
Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo 113-0033, Japan.
Kitami
Toshiaki
T
Nagahama
Masami
M
Tagaya
Mitsuo
M
Hori
Seiji
S
Kakizuka
Akira
A
Mizuno
Yoshikuni
Y
Hattori
Nobutaka
N
D000251:Adenosine Triphosphatases; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D007976:Leupeptins / Q000378:metabolism; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D017434:Protein Structure, Tertiary; D013347:Subcellular Fractions / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde