[A challenge for revealing common molecular mechanisms underlying neurodegenerative disorders].
Many neuodegenerative disorders manifest disease-specific phenotypes, and thus it was thought impossible to deduce a common molecular mechanism underlying many, if not all, neurodegenerative disorders. However, protein aggregates and vacuoles are almost universally found in degenerating neurons, suggesting the existence of similar molecular processes in neuronal cell death. In 1994, we identified the gene responsible for Machado-Joseph disease (MJD). Not only MJD but also another 8 inherited neurodegenerative diseases, including Huntington's disease are caused by the expansion of CAG repeats encoding polyglutamines. Indeed, we have shown that polyglutamines have the ability to self-aggregate and induce neurodegeneration and neuronal cell death, leading to a proposal of 'polyglutamine disease'. Furthermore, we have identified ter94/VCP, a member of the AAAAT-Pase, as a key molecule in neurodegeneration. VCP co-localizes not only with polyglutamine aggregates but also other protein aggregates and Lewy bodies. Moreover, profound deficits in its ATPase activity are found to severely affect ER quality control, leading to abnormal ER expansion and cell death. These lines of evidence indicate that VCP functions not only as a common sensor for abnormal protein accumulations but also as a mediator of neurodegenerative phenotypes; excessive accumulation of abnormal proteins may inactivate VCP's ATPase 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.
Kakizuka
Akira
A
Department of Functional Biology, Kyoto University Graduate School of Biostudies.
D000251:Adenosine Triphosphatases; D018797:Cell Cycle Proteins / Q000235:genetics; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics*; D006801:Humans; D010455:Peptides / Q000235:genetics; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; D010455:Peptides; C097188:polyglutamine; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein