Abstract
Neuronal cell death, abnormal protein aggregates, and cytoplasmic vacuolization are major pathologies observed in many neurodegenerative disorders such as the polyglutamine (polyQ) diseases, prion disease, Alzheimer disease, and the Lewy body diseases, suggesting common mechanisms underlying neurodegeneration. Here, we have identified VCP/p97, a member of the AAA+ family of ATPase proteins, as a polyQ-interacting protein in vitro and in vivo, and report on its characterization. Endogenous VCP co-localized with expanded polyQ (ex-polyQ) aggregates in cultured cells expressing ex-polyQ, with nuclear inclusions in Huntington disease patient brains, and with Lewy bodies in patient samples. Moreover, the expression of VCP mutants with mutations in the 2nd ATP binding domain created cytoplasmic vacuoles, followed by cell death. Very similar vacuoles were also induced by ex-polyQ expression or proteasome inhibitor treatment. These results suggest that VCP functions not only as a recognition factor for abnormally folded proteins but also as a pathological effector for several neurodegenerative phenotypes. VCP may thus be an ideal molecular target for the treatment of neurodegenerative disorders. Cell Death and Differentiation (2001) 8, 977–984
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Acknowledgements
We thank H Yoshii and M Sugimoto for secretarial assistance in the preparation of this manuscript. We thank G Sobue (Nagoya University) for postmortem brain samples with HD, and M Baba and T Iwatsubo (Tokyo University) for postmortem brain samples for DLB. This work was supported in part by research grants from the Ministry of Education, Science, Sports, and Culture of Japan, and the Ministry of Welfare of Japan, the Yamanouchi Foundation for Research on Metabolic Disorders, the Naito Foundation, and the Uehara Foundation.
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Hirabayashi, M., Inoue, K., Tanaka, K. et al. VCP/p97 in abnormal protein aggregates, cytoplasmic vacuoles, and cell death, phenotypes relevant to neurodegeneration. Cell Death Differ 8, 977–984 (2001). https://doi.org/10.1038/sj.cdd.4400907
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DOI: https://doi.org/10.1038/sj.cdd.4400907
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