Molecular mechanisms of neurodegeneration

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To date, 9 polyglutamine diseases including dentatorubral-pallidoluysian atrophy (DRPLA) have been identified to be caused by abnormal expansion of CAG repeats coding for polyglutamine stretches. To elucidate the molecular mechanisms of neurodegeneration in polyglutamine diseases, we first attempted to create mouse models that closely replicate pathophysiologic processes in human brains. To accomplish this aim, we tried to create transgenic mice carrying a full-length mutant human DRPLA gene as a single copy gene. The Q129 mouse carrying a largely expanded CAG repeats (129) showed strong neurological phenotypes including ataxia, myoclonus and epilepsy. Based on detailed neuropathological analyses, we found that neuronal loss was not detected despite the strong phenotypes, suggesting that neuronal death is not the essential processes in neurodegeneration. We furthermore found that intranuclear accumulation of mutant DRPLA proteins is the essential neuropathological findings. This observ … More ation raises the possibility that nuclear dysfunction underlies the neurodegeneration in polyglutamine diseases. Based on cell culture systems, we demonstrated that CREB-dependent transcriptional activation is severely suppressed employing a reporter system. We further demonstrated activation of endogenous c-fos transcription is also strongly suppressed by expanded polyglutamine stretches. To further elucidate the mechanisms of transcriptional dysregulation in polyglutamine diseases, we have conducted detailed expression profiling analyses using Q76, Q113 and Q129, carrying a full-length mutant human DRPLA gene as a single copy gene with various lengths of expanded CAG repeats (76, 113 and 129 repeat units). We found that substantial number of genes were suppressed in time-dependent and repeat length-dependent manners. Among the down-regulated genes, many cAMP-responsive genes (c-fos and EGR1) are included Taken together, we have demonstrated that suppression of CREB-dependent transcriptional activation is strongly suppressed by expanded polyglutamine stretches and restoration of such suppression is the target for developing therapeutic approaches for polyglutamine diseases. Less