title: [Dentatorubral-pallidoluysian atrophy (DRPLA)--discovery of the disease, DRPLA gene and the pathophysiology].
abstract: The clinical entity of dentatorubral-pallidoluysian atrophy (DRPLA) was discovered and established in Japan. The characteristic clinical genetic features of DRPLA including prominent anticipation prompted us to search the genes carrying CAG repeats as the candidate genes for DRPLA. Based on this approach, the DRPLA gene was discovered by two independent Japanese groups in 1994. Given that DRPLA is caused by expansion of CAG repeats, the molecular mechanisms of the anticipation and the broad clinical presentations of DRPLA depending on the age at onset are clearly understood as a function of the size and the instability of the CAG repeats. Recent studies have suggested that mutant proteins with expanded polyglutamine stretches have "gain-of-toxic" functions to neuronal cells. The molecular mechanisms of the "toxic" functions, however, have not been identified. Based on the recent findings that nuclear transport of the mutant proteins carrying expanded polyglutamine stretches is important in the pathogenesis, we screened nuclear proteins which bind to expanded polyglutamine stretches. We found that expanded polyglutamine stretches bind to TAFII130, a TATA-binding protein-associated factor, and interfere with CREB-dependent transcriptional activation. Since CREB-dependent transcriptional activation plays essential roles in neuronal survival and plasticity, such interference is expected to lead to neuronal dysfunction.
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University.
authors.forename: S
authors.initials: S
authors.lastname: Tsuji
mesh_terms: D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics / Q000503:physiopathology; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D019680:Trinucleotide Repeat Expansion
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D010455:Peptides; C101882:TAF4 protein, human; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D014157:Transcription Factors; C097188:polyglutamine