Mutant ataxin-1 (Atxn1), which causes spinocerebellar ataxia type 1 (SCA1), binds to and impairs the function of high-mobility group box 1 (HMGB1), a crucial nuclear protein that regulates DNA architectural changes essential for DNA damage repair and transcription. In this study, we established that transgenic or virus vector-mediated complementation with HMGB1 ameliorates motor dysfunction and prolongs lifespan in mutant Atxn1 knock-in (Atxn1-KI) mice. We identified mitochondrial DNA damage repair by HMGB1 as a novel molecular basis for this effect, in addition to the mechanisms already associated with HMGB1 function, such as nuclear DNA damage repair and nuclear transcription. The dysfunction and the improvement of mitochondrial DNA damage repair functions are tightly associated with the exacerbation and rescue, respectively, of symptoms, supporting the involvement of mitochondrial DNA quality control by HMGB1 in SCA1 pathology. Moreover, we show that the rescue of Purkinje cell dendrites and dendritic spines by HMGB1 could be downstream effects. Although extracellular HMGB1 triggers inflammation mediated by Toll-like receptor and receptor for advanced glycation end products, upregulation of intracellular HMGB1 does not induce such side effects. Thus, viral delivery of HMGB1 is a candidate approach by which to modify the disease progression of SCA1 even after the onset. Synopsis: Spinocerebellar ataxia type 1 (SCA1) is an intractable neurodegenerative disease. A gene therapy approach targeting HMGB1 against the SCA1 pathology in a mutant Atxn1 knock-in mouse model prolonged lifespan and correct DNA damage defects in the mitochondrial genome. Mitochondrial genome DNA damage is repaired by HMGB1. The abnormal gene expression profile of Purkinje cells is partially corrected by HMGB1. The mean and maximum lifespan of Atxn1-KI mice are substantially prolonged (by 60-70%) by means of the gene therapy of HMGB1. Spinocerebellar ataxia type 1 (SCA1) is an intractable neurodegenerative disease. A gene therapy approach targeting HMGB1 against the SCA1 pathology in a mutant Atxn1 knock-in mouse model prolonged lifespan and correct DNA damage defects in the mitochondrial genome.
- DNA damage repair