[Mechanisms of neurodegeneration in polyglutamine diseases]

Neurodegenerative diseases are characterized by (1) age of onset usually in late adulthood, (2) insidious onset and gradual progression, (3) neuronal loss in particular regions of the nervous system with the distribution being unique to each neurodegenerative disease, and (4) familial occurrence is occasionally encountered in theses diseases, but the majority is "sporadic". Recent progresses in molecular genetic studies have enabled to identify the causative genes. Among the hereditary neurodegenerative diseases, polyglutamine diseases are of particular interest, because common pathophysiologic mechanisms are considered to underlie the neurodegenerative processes. In transgenic mice carrying a full-length mutant DRPLA gene, obvious neuronal loss was not observed despite the severe neurological phenotypes. We have found intranuclear accumulation of mutant proteins with expanded polyglutamine stretches leads to "reversible" transcriptional dysregulation through interaction of expanded polyglutamine stretches with TAF130, a transcriptional coactivator. The fact that there is no obvious neuronal loss in the transgenic mice indicate that the processes of neurodegeneration are "reversible" neuronal dysfunctions, and, furthermore, strongly encourages development of therapeutic approaches for neurodegenerative diseases.