| Budget Amount *help |
¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2003: ¥5,400,000 (Direct Cost: ¥5,400,000)
Fiscal Year 2002: ¥9,600,000 (Direct Cost: ¥9,600,000)
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| Research Abstract |
In neurodegenerative disorders, protein aggregates and vacuoles are almost universally found in degenerating neurons, suggesting the existence of similar molecular processes in, neuronal cell death. Indeed, 9 inherited neurodegenerative diseases, including Huntington disease have been shown to be caused by the expansion of CAG repeats encoding polyglutamines. We have identified VCP, a member of the AAA ATPase, as a key molecule in neurodegeneration. Namely, 1) VCP co-localizes with polyglutamine aggregates and other protein aggregates such as Lewy bodies in Parkinson disease; 2) Profound deficits in VCP's ATPase activity are found to severely affect ER quality control, leading to abnormal ER expansion and cell death, phenotypes frequently observed in many neurodegenerative diseases; 3) VCP has a potential to unfold misfolded proteins; 4) several amino acid in VCP are modified; 5) Modified VCP shows different ATPase activities. These lines of evidence raise the possibility that excessive accumulation of abnormal proteins may inactivate, VCP's ATPase via its (mis)modification in several neurodegenerative disorders, eventually leading to the neurodegenerations. A proper regulation of VCP function is thus proposed to lead to novel treatments that are effective in a broad spectrum of neurodegenerative diseases.
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