HMGB 1 facilitates repair of mitochondrial DNA damage and extends the lifespan of mutant ataxin‐1 knock‐in mice

Abstract

Mutant ataxin‐1 (Atxn1), which causes spinocerebellar ataxia type 1 ( SCA 1), binds to and impairs the function of high‐mobility group box 1 ( HMGB 1), 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 HMGB 1 ameliorates motor dysfunction and prolongs lifespan in mutant Atxn1 knock‐in (Atxn1‐ KI ) mice. We identified mitochondrial DNA damage repair by HMGB 1 as a novel molecular basis for this effect, in addition to the mechanisms already associated with HMGB 1 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 HMGB 1 in SCA 1 pathology. Moreover, we show that the rescue of Purkinje cell dendrites and dendritic spines by HMGB 1 could be downstream effects. Although extracellular HMGB 1 triggers inflammation mediated by Toll‐like receptor and receptor for advanced glycation end products, upregulation of intracellular HMGB 1 does not induce such side effects. Thus, viral delivery of HMGB 1 is a candidate approach by which to modify the disease progression of SCA 1 even after the onset. image Spinocerebellar ataxia type 1 ( SCA 1) is an intractable neurodegenerative disease. A gene therapy approach targeting HMGB 1 against the SCA 1 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 HMGB 1. The abnormal gene expression profile of Purkinje cells is partially corrected by HMGB 1. The mean and maximum lifespan of Atxn1‐ KI mice are substantially prolonged (by 60–70%) by means of the gene therapy of HMGB 1.