Basic Research for Development of the Polyglutamine Disease Therapeutics by HMGB proteins

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Neurodegnerative diseases are caused by aggregation of misfiled disease proteins inside or outside of neurons. The disease proteins are suspected to interact with physiological cellular proteins before aggregation, and to dysfunction or decrease the normal proteins. In polyglutamine diseases including 9 neurodegenerative diseases such as Huntington's disease and familial spinocerebellar ataxias, it is known that nuclear translocation of the disease proteins is essential for the pathology. We examined quantitative change of soluble nuclear proteins through proteome analysis, and found that HMGB proteins are reduced in two polyglutamine diseases. HMGB proteins play critical roles for high architectural change of genomic DNA, thus they are essential for recombination, damage repair, and transcription. We found the reduction of soluble nuclear HMGB proteins leads to an increase of DNA damage signals and a reduction of general transcription. Furthermore, we found that supplementation of HMGB1 protein rescues neurodegeneration in fly models.From these results, we propose dysfunction of DNA damage repair as a new critical pathology of polyglutamine diseases. Considering that mutations of DNA damage repair genes cause aging disorders, we might be able to hypothesize that polyglutamine diseases are secondary accelerated aging due to the accumulation of conformationally abnormal protins in neurons.