Elucidation of molecular mechanisms of neurodegenerative diseases caused by expansion of CAG repeats

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This study was aimed to elucidate molecular mechanisms ofheurodegetterative diseases caused by expansion of CAG repeats. To accomplish this aim, two strategies! have been employed; 1. Molecular cloning of CAG repeat-containing cDNAs expressed in human brains as the candidate genes for hereditary neurodegenerative diseases, and 2. Elucidation of mechanisms of neurodegeherati6n : caused by expahded; CAG repeats coding for polyglutarnine stretches. As the former approach, we screened human brain cDNA libraries using (CAG)10 or (CAG)20 oligbnucleotide probes. Excluding overlapping clones, we have identified 92 independent cDNA clones as the CAG repeat-containing CDNA clones. Among the 92 clones, we selected 41 clones as the CDNA clones carrying > 10 CAG repeats. These cDNA clones are beihg screeried as the candfdate genes for hereditary neurddegenerative disease. As the latter approach, we focused our study to elucidate the mechanisms of nuclear dysfunctions as a result of nuclear transport and intranuclear accumulation of mutant protein carrying expanded polyglutamine stretches. We performed expression pro filing of Q129 mice catfying a full-length mutant DRPEA gene carrying a largely expanded GAG repeat (129 repeat units) that have been developed in our laboratory. Detailed expression pro filing analysis revealed 78 down-regulated genes and 16 up-regulated genes. The alteration of expression levels is observed as a time-dependent manner. Many cAMP-resporisive genes were included in the dpwh-regulated genes, confirming our hypothesis that CREB-dependent transcriptional activation is suppressed by expanded polyglutamine stretches.