RpA1 ameliorates symptoms of mutant ataxin-1 knock-in mice and enhances DNA damage repair.
DNA damage and repair is a critical domain of many neurodegenerative diseases. In this study, we focused on RpA1, a candidate key molecule in polyQ disease pathologies, and tested the therapeutic effect of adeno-associated virus (AAV) vector expressing RpA1 on mutant Ataxin-1 knock-in (Atxn1-KI) mice. We found significant effects on motor functions, normalized DNA damage markers (γH2AX and 53BP1), and improved Purkinje cell morphology; effects that lasted for 50 weeks following AAV-RpA1 infection. In addition, we confirmed that AAV-RpA1 indirectly recovered multiple cellular functions such as RNA splicing, transcription and cell cycle as well as abnormal morphology of dendrite and dendritic spine of Purkinje cells in Atxn1-KI mice. All these results suggested a possibility of gene therapy with RpA1 for SCA1.
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Juliana Bosso
JB
Taniguchi
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Kanoh
K
Kondo
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Kyota
K
Fujita
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Xigui
X
Chen
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Hidenori
H
Homma
Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Takeaki
T
Sudo
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Ying
Y
Mao
Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo113-8510, Japan.
Kei
K
Watase
Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Toshihiro
T
Tanaka
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Kazuhiko
K
Tagawa
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Takuya
T
Tamura
Division of Neurology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0496, Japan|Center for Gene & Cell Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo108-8639, Japan
Shin-Ichi
SI
Muramatsu
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.|Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo113-8510, Japan.
Hitoshi
H
Okazawa
D000818:Animals; D000067696:Ataxin-1 / Q000235:genetics*; D002453:Cell Cycle; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D000229:Dependovirus; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D015316:Genetic Therapy; D051379:Mice; D009154:Mutation; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D012313:RNA / Q000378:metabolism; D012326:RNA Splicing; D051716:Replication Protein A / Q000378:metabolism*; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D014158:Transcription, Genetic
D000067696:Ataxin-1; C000593750:Atxn1 protein, mouse; D051716:Replication Protein A; C497168:Rpa1 protein, mouse; D012313:RNA; D004247:DNA