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

神经退行性疾病是由神经元内部或外部的错误疾病蛋白聚集引起的。疾病蛋白质被怀疑在聚集之前与生理细胞蛋白质相互作用，并使正常蛋白质功能障碍或减少。在包括9种神经变性疾病如亨廷顿病和家族性脊髓小脑共济失调的多聚谷氨酰胺疾病中，已知疾病蛋白质的核转位对于病理学是必需的。我们通过蛋白质组分析检测了可溶性核蛋白的数量变化，发现HMGB蛋白在两种多聚谷氨酰胺疾病中减少。HMGB蛋白在基因组DNA的高度结构改变中起着关键作用，因此它们对于重组、损伤修复和转录是必不可少的。我们发现可溶性核HMGB蛋白的减少导致DNA损伤信号的增加和一般转录的减少。此外，我们发现补充HMGB1蛋白可以挽救果蝇模型中的神经退行性变。根据这些结果，我们提出DNA损伤修复功能障碍是多聚谷氨酰胺疾病的一个新的关键病理学。考虑到DNA损伤修复基因的突变导致衰老障碍，我们可能能够假设多聚谷氨酰胺疾病是由于构象异常蛋白在神经元中的积累而引起的继发性加速衰老。

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.