Chorea-acanthocytosis and mitophagy: clarifying the molecular mechanisms of the disease and developing methods to prevent neurodegeneration

• Project/Area Number: 17H04250
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Kagoshima University
• Principal Investigator: Sano Akira 鹿児島大学, 医歯学域医学系, 教授 (30178800)
• Co-Investigator(Kenkyū-buntansha): 中村 雅之 鹿児島大学, 医歯学域医学系, 准教授 (90332832)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2018: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2017: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: 有棘赤血球舞踏病 / マイトファジー / chorein / VPS13A / 創始者効果 / 神経変性 / VPS13A遺伝子 / Chorein

Outline of Final Research Achievements

Selective autophagy for impaired mitochondria is known as mitophagy, by which mitochondrial quality is preserved. Chorein, a protein responsible for chorea-acanthocytosis, was suggested to be involved in mitophagy-mediated mitochondrial quality control mechanisms. It was suggested that the neurodegeneration in chorea-acanthocytosis may be due in part to a disruption of mitophagy.
We found that patients with chorea-acanthocytosis exhibited a variety of psychiatric symptoms, including cognitive decline. Approximately 55% of the mutations in Japanese patients with ChAc carried two major mutations. These mutations were localized in Tokyo and west side of Japan and the partial founder effects were suggested.

Academic Significance and Societal Importance of the Research Achievements

有棘赤血球舞踏病は、国際的には日本人に多いとされる稀な遺伝性神経変性疾患である。今回の研究で、有棘赤血球舞踏病が認知機能障害を含む多彩な精神症状を呈することが明らかとなった。また、有棘赤血球舞踏病の病因にミトコンドリアの品質維持機構の破綻が関与している可能性が示唆された。有棘赤血球舞踏病が多彩な精神症状を呈することからも、choreinとマイトファジーが他の精神神経疾患と関連する可能性と、その破綻した機構の回復が多くの精神神経疾患の分子的な治療の一端となる可能性がある。

Research Products

• [Journal Article] Discriminating chorea-acanthocytosis from Huntington's disease with single-case voxel-based morphometry analysis. (2020)
  • Author(s): Suzuki F, Sato N, Ota M, Sugiyama A, Shigeyamay, Morimoto E, Kimura Y, Wakasugi N, Takahashi Y, Futamura A, Kawamura M, Ono K, Nakamura M, Sano A, Watanabe Masako, Mathuda H, Abe O
  • Journal Title: J Neurol Sci. Volume: 408 Pages: 116545-116545
  • DOI: 10.1016/j.jns.2019.116545
  • Peer Reviewed
• [Journal Article] Novel VPS13A gene mutations in a South Asian, Indian patient with chorea-acanthocytosis. (2020)
  • Author(s): Futamura A, Nakamura M, Kawamura M Sano A, Ono K
  • Journal Title: Neurology India Volume: 68 Pages: 206-208
  • DOI: 10.4103/0028-3886.279653
  • Peer Reviewed
• [Journal Article] Chorea-acanthocytosis with a novel mutation in the vacuolar protein sorting 13 homolog a gene: A case report. (2020)
  • Author(s): Tada Y, Hamaguchi T, Ikeda Y, Iwasa K, Nishida Y, Nakamura M, Sano A, Yamada M
  • Journal Title: Journal of the Neurological Sciences Volume: 412 Pages: 116731-116731
  • DOI: 10.1016/j.jns.2020.116731
  • Peer Reviewed
• [Journal Article] Novel pathogenic XK mutations in McLeod syndrome and interaction between XK protein and chorein (2019)
  • Author(s): Yuka Urata, Masayuki Nakamura, Natsuki Sasaki, et al.
  • Journal Title: Neurology. Genetics Volume: 5
  • DOI: 10.1212/nxg.0000000000000328
  • Peer Reviewed / Open Access
• [Journal Article] Novel pathogenic VPS13A gene mutations in Japanese patients with chorea-acanthocytosis (2019)
  • Author(s): Yoshiaki Nishida, Masayuki Nakamura, Yuka Urata, et al.
  • Journal Title: Neurol. Genet. Volume: 5
  • DOI: 10.1212/nxg.0000000000000332
  • NAID: 120006859409
  • Peer Reviewed / Open Access
• [Journal Article] A patient with McLeod syndrome showing involvement of the central sensorimotor tracts for the legs. (2019)
  • Author(s): Murakami T, Abe D, Matsumoto H, Tokimura R, Abe M, Tiksnadi A, Kobayashi S, Kaneko C, Urata Y, Nakamura M, Sano A, Ugawa Y
  • Journal Title: BMC neurology Volume: 19 Pages: 1526-1529
  • DOI: 10.1186/s12883-019-1526-9
  • Peer Reviewed / Open Access
• [Journal Article] 神経有棘赤血球症の遺伝子変異と分子病態 (2019)
  • Author(s): 中村雅之
  • Journal Title: MDSJ Letters Volume: 12 Pages: 57-60
  • NAID: 40022095831
  • Open Access
• [Journal Article] 精神症状を伴う神経変性疾患 (2019)
  • Author(s): 中村雅之、佐野 輝
  • Journal Title: 臨床精神医学 Volume: 48 Pages: 75-81
• [Presentation] Molecular diagnosis and symptoms of the six cases of McLeod syndrome. (2018)
  • Author(s): Urata Y, Nakamura M, Hiwatashi H, Yokoyama I, Meguro K, Sano A
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry
  • Int'l Joint Research
• [Presentation] Novel pathogenic mutations in the VPS13A gene in Japanese patients with Chorea-acanthocytosis and clinical diversities. (2018)
  • Author(s): Nishida Y, Nakamura M, Sano A
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry
• [Book] 有棘赤血球舞踏病、神経変性疾患ハンドブックー神経難病へのエキスパートアプローチ (2018)
  • Author(s): 中村雅之、佐野 輝
  • Total Pages: 13
  • Publisher: 南江堂
  • ISBN: 4524256172