[DNA repair and neurodegeneration: a common pathology shared by polyglutamine diseases]

Nuclear dysfunctions have been implicated in the pathology of polyglutamine diseases, while the details remain unclear. By employing various omics approaches, we have identified target molecules of mutant polyglutamine proteins in the nucleus. Proteome analysis of soluble nuclear proteins identified decreased HMGB1/2 in vulnerable neurons of Huntington's disease (HD) and spinocerebellar ataxia type 1 (SCA1). Interactome analysis unraveled Ku70 as a direct binding partner of mutant huntingtin. DNA damage repair is significantly impaired by interaction of mutant polyglutamine proteins with HMGB or Ku70, and the functional rescue of these molecules alleviated symptoms and pathologies of HD and SCA1. These results strongly suggest that impairment of DNA damage repair is a common pathology shared by multiple polyglutamine diseases.