title: [Molecular mechanisms of neurodegeneration in dentatorubral-pallidoluysian atrophy (DRPLA)].
abstract: Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by various combinations of cerebellar ataxia, choreoathetosis, myoclonus, epilepsy, dementia and psychiatric symptoms. With the discovery of the gene for DRPLA in 1994, molecular mechanisms of neurodegeneration has been intensively investigated. Expression of truncated DRPLA proteins in cultured cell has been shown to result in aggregate body formation and apoptosis. We have developed transgenic mice for DRPLA (Q129 mice). The Q129 mice showed a severe neurological phenotype characterized by ataxia, myoclonus and seizures. Although numerous neuronal intranuclear inclusions (NIIs) were observed in the brain, obvious neuronal loss was not observed. NIIs, however, appeared much later than the phenotypic presentations, and intranuclear accumulation (diffuse nuclear staining) of mutant proteins was the earliest phenomenon. These results suggest that "neuronal dysfunction", but not "neuronal cell death", is responsible for the phenotypes. Hypothesizing that nuclear proteins interacting with expanded polyglutamine stretches are involved in the pathogenesis, we found that that expanded polyglutamine stretches preferentially bind to TAF130, a cofactor involved in CREB-dependent transcriptional activation, and strongly suppressed CREB-dependent transcriptional activation. Taken together, these findings suggest that the interference of CREB-dependent transcription by expanded polyglutamine stretches is involved in the neuronal dysfunction in polyglutamine diseases.
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University.
authors.forename: S
authors.initials: S
authors.lastname: Tsuji
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics* / Q000473:pathology*; D009410:Nerve Degeneration / Q000235:genetics*; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding; D015533:Transcriptional Activation
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C095278:atrophin-1; C097188:polyglutamine