Summary of Research Project Results under JSPS FY2004
"Research for the Future Program"

1. Research Institution   The University of Tokyo
2. Research Area Life Sciences
3. Research Field Genome Research
4. Term of Project FY 2000 - FY 2004
5. Project Number 00L01404
6. Title of Project Identification of Genes Involved in Brain Diseases

7. Project Leader

Name Institution, Department Title of Position
Shoji, Tsuji The University of Tokyo, Graduate School of Medicine Professor

8. Core Members

Name Institution, Department Title of Position
Jun, Goto The University of Tokyo Hospital Lecturer

9. Summary of Research Results

The project focused on identification of genes involved in brain diseases based on genome analyses. The focused diseases include inherited spinocerebellar ataxias (autosomal recessive as well as autosomal dominant forms), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), multiple system atrophy (MSA). To promote the genome research, we first established a high-throughput linkage analysis system utilizing microsatellite markers. This system allowed us to rapidly identify the candidate regions of causative genes. The project has focused on 1 single gene diseases and 2 diseases with complex trait. As the result of approaches toward single gene diseases, we identified the causative gene, APTX, for early-onset ataxia with hypoalbuminemia and ocular motor apraxia (EAOH), a common form or autosomal recessive spinocerebellar ataxia in Japan, based on the linkage analysis and linkage disequilibrium mapping. We furthermore demonstrated that the gene product, aprataxin, functions as an enzyme involved in the single stranded DNA break-repair system. The discovery has opened a new field of molecular pathogenesis of spinocerebellar ataxias. For autosomal dominant ataxia, we have mapped a locus for an autosomal dominant ataxia to chromosome 3p26.1-25.3. Genome-wide linkage analysis of CARASIL has revealed a candidate locus. Positional cloning approach is in progress. As the approach toward neurodegenerative diseases with complex trait, we have focused on MSA (multiple system atrophy), which is the most common form of a sporadic ataxia in Japan. We have recently identified pathologically proven familial cases of MSA. Upon a nation-wide survey, 10 familial cases of MSA have been identified. Non-parametric linkage analysis of familial MSA cases has revealed several candidate loci which will be useful for the association studies on sporadic MSA cases. Based on studies on cell culture systems and transgenic mice, the molecular pathogenesis of polyglutamine diseases has been shown to be caused by suppression of transcriptional activation as a result of intranuclear accumulation of mutant proteins with expanded polyglutamine stretches.

10. Key Words

( 1 ) brain diseases ( 2 ) genome analysis ( 3 ) spinocerebellar ataxia
( 4 ) aprataxin ( 5 ) CARASIL ( 6 ) MSA
( 7 ) DNA repair ( 8 ) polyglutamine diseases