title: HMGB1 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 (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.
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku Tokyo, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku Tokyo, Japan.
authors.forename: Kyota
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tagawa
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku Tokyo, Japan.
authors.forename: Xigui
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku Tokyo, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Homma
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku Tokyo, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Sasabe
authors.affiliation: Department of Neurology, The University of Tokyo, Bunkyo-ku Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Shimizu
authors.affiliation: Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku Tokyo, Japan.
authors.forename: Shigeomi
authors.initials: S
authors.lastname: Shimizu
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku Tokyo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Tamura
authors.affiliation: Department of Neurology, Jichi Medical University, Shimotsuke Tochigi, Japan.
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Muramatsu
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku Tokyo, Japan Center for Brain Integration Research, Tokyo Medical and Dental University, Bunkyo-ku Tokyo, Japan okazawa-tky@umin.ac.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okazawa
mesh_terms: D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008136:Longevity; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000378:metabolism
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; C000593751:Atxn1 protein, rat; D004272:DNA, Mitochondrial; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins
keywords: AAV; DNA damage repair; HMGB1; SCA1; mitochondria