Pathophysiology of white matter dystrophy via mitochondrial dysfunction caused by AARS2 mutation

• Project/Area Number: 18K15448
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Kyoto University
• Principal Investigator: Jingami Naoto 京都大学, 医学研究科, 助教 (80808460)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: AARS2 / 白質ジストロフィー / LKENP / ミトコンドリア / 卵巣機能障害 / 脳血管障害 / 白質障害 / 認知症 / ミエリン / 卵巣機能異常

Outline of Final Research Achievements

An abnormality in the gene encoding the mitochondrial alanyl tRNA synthetase enzyme, AARS2, causes white matter dystrophy. White matter dystrophy is a progressive degeneration of the cerebral white matter. There is no specific treatment for this disease, and the development of a cure is still awaited. In this study, we analyzed why AARS2 mutations cause white matter dystrophy or neuropathy via mitochondrial abnormalities. We analyzed the differences in mitochondrial function by expressing AARS2 in an experimental cell model and inhibiting its expression using RNA interference.

Academic Significance and Societal Importance of the Research Achievements

白質ジストロフィーはその臨床的特徴の多様性や複雑性により診断が困難な場合が多い。 生活習慣病などに起因する脳血管障害等環境的要因や低酸素血症からの回復後に生じる遅発性低酸素脳症など様々な要因が背景に潜在する場合がある。ただし、原因が不明で、特に若年発症例では遺伝的要因が関与することがある。本研究では白質ジストロフィーを呈する原因遺伝子の一つであるAARS2が神経障害を呈するプロセスを解析し、ミトコンドリア機能の障害が関与することが想定された。白質ジストロフィーの治療標的に本研究内容が生かされる可能性がある。

Research Products

• [Journal Article] Two-Point Dynamic Observation of Alzheimer’s Disease Cerebrospinal Fluid Biomarkers in Idiopathic Normal Pressure Hydrocephalus (2019)
  • Author(s): Naoto Jingami, Kengo Uemura, Megumi Asada-Utsugi, Akira Kuzuya, Shigeki Yamada, Masatsune Ishikawa, Takashi Kawahara, Takuya Iwasaki, Masamichi Atsuchi, Ryosuke Takahashi, Ayae Kinoshita
  • Journal Title: Journal of Alzheimer's Disease Volume: 72 Issue: 1 Pages: 271-277
  • DOI: 10.3233/jad-190775
  • NAID: 120006767911
  • Peer Reviewed / Open Access
• [Journal Article] Anterior Choroidal Artery Infarction Evaluated with 123I-Imp Single-Photon Emission Computed Tomography and 7 Tesla Magnetic Resonance Imaging (2019)
  • Author(s): Te-Hsiung Wang, Naoto Jingami, Tomohisa Okada, Tomoyuki Yunoki, Shigeru Ohtsuru, Kaoru Koike
  • Journal Title: Journal of Stroke and Cerebrovascular Diseases Volume: 28 Issue: 5 Pages: e51-e52
  • DOI: 10.1016/j.jstrokecerebrovasdis.2019.02.007
  • Peer Reviewed
• [Presentation] 間歇型一酸化炭素中毒による認知機能低下に対する高気圧酸素治療の有効性 (2022)
  • Author(s): 陣上直人、新田孝幸、川竹絢子、荒深桜子、橋本健之、堀晃暢、吉原雄二郎、小林勝哉、石黒義孝、趙晃済、柚木知之、村井俊哉、高橋良輔、大鶴繁
  • Organizer: 第41回日本認知症学会学術集会
• [Presentation] Two-point Dynamic Observation of Alzheimer’s Disease Cerebrospinal Fluid Biomarkers in Idiopathic Normal Pressure Hydrocephalus (2020)
  • Author(s): Naoto Jingami, Kengo Uemura, Megumi Asada, Akira Kuzuya, Ryosuke Takahashi, and Ayae Kinoshita
  • Organizer: Alzheimer's Association International Conference 2020
  • Int'l Joint Research
• [Presentation] The Organization of Stroke Care in Japan (2020)
  • Author(s): Naoto Jingami
  • Organizer: Cerebrovascular Conference
• [Presentation] Steroid Therapy Shows Beneficial Effect on the Case of ARDS Caused by Antisynthetase Syndrome. (2019)
  • Author(s): Takahiko Tsutsumi, Naoto Jingami, Manabu Shimoto, Kosai Cho, Shigeru Otsuru, Kaoru Koike
  • Organizer: 18th International Conference on Emergency Medicine
  • Int'l Joint Research
• [Book] 画像で診る遺伝性白質疾患 診断の手引き (2021)
  • Author(s): 厚生労働科学研究費補助金難治性疾患政策研究事業遺伝性白質疾患・知的障害をきたす疾患の診断・治療・研究システム構築班
  • Total Pages: 176
  • Publisher: 診断と治療社
  • ISBN: 9784787824714