Elucidation of molecular mechanisms and development of surrogate markers for multiple system atrophy caused by COQ2 mutations

• Project/Area Number: 26253054
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: The University of Tokyo
• Principal Investigator: Tsuji Shoji 東京大学, 医学部附属病院, 教授 (70150612)
• Co-Investigator(Kenkyū-buntansha): 三井 純 東京大学, 医学部附属病院, 助教 (70579862)
• Co-Investigator(Renkei-kenkyūsha): GOTO Jun 東京大学, 医学部附属病院, 准教授 (10211252) ; MITSUI Jun 東京大学, 医学部附属病院, 助教 (70579862)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥42,250,000 (Direct Cost: ¥32,500,000、Indirect Cost: ¥9,750,000); Fiscal Year 2016: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000); Fiscal Year 2015: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000); Fiscal Year 2014: ¥27,950,000 (Direct Cost: ¥21,500,000、Indirect Cost: ¥6,450,000)
• Keywords: 多系統萎縮症 / COQ2 / フラックスアナライザー / coenzyme Q10 / ミトコンドリア / 神経分子病態学 / shojitsuji-tky / ミトコンドリア機能

Outline of Final Research Achievements

In our previous studies, we found that COQ2 mutations are associated with familial as well as sporadic multiple system atrophy (MSA). To quantitatively evaluate the altered functions of COQ2 coding for an enzyme in the biosynthesis of CoQ10, we measured oxygen consumption rates (OCR) of yeast harboring mutant human COQ2 cDNA employing a Flux Analyzer. We prepared mutant yeast with a deletion of yeast COQ2 gene. We then transformed the yeast with mutant human COQ2 cDNA, and measured the OCRs of these yeast strains. We demonstrated that OCRs of yeast harboring V393A, a susceptibility variant for sporadic MSA, or M128V, a causative mutation for familial MSA, are significantly decreased. The results suggest that OCR measurement may be utilized as a surrogate marker for MSA.

Research Products

• [Journal Article] Three-year follow-up of high-dose ubiquinol supplementation in a case of familial multiple system atrophy with compound heterozygous COQ2 mutations. (2017)
  • Author(s): Mitsui J, Koguchi K, Momose T, Takahashi M, Matsukawa T, Yasuda T, Tokushige S, Ishiura H, Goto J, Nakazaki S, Kondo T, Ito H, Yamamoto Y and Tsuji S.
  • Journal Title: Cerebellum Volume: - Issue: 3 Pages: 1-9
  • DOI: 10.1007/s12311-017-0846-9
  • Peer Reviewed / Open Access
• [Presentation] Functional Analysis of COQ2 V393A variant associated with Multiple system atrophy based on measurement of Oxygen Consumption Rate of Transformed Yeasts Carrying human COQ2 cDNAs． (2016)
  • Author(s): Tsutomu Yasuda, Takashi Matsukawa, Jun Mitsui, Shoji Tsuji
  • Organizer: International Congress of Human Genetics
  • Place of Presentation: Kyoto
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] Functional Analysis of COQ2 V393A variant associated with Multiple system atrophy based on measurement of Oxygen Consumption Rate of Transformed Yeasts Carrying human COQ2 cDNAs. (2016)
  • Author(s): Tsutomu Yasuda, Takashi Matsukawa, Jun Mitsui, Shoji Tsuji
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2016-04-03
  • Int'l Joint Research