Search for targeted therapies for alpha-synuclein-induced neurotoxicity in STXBP1 encephalopathy

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07855
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Chiyonobu Tomohiro 京都府立医科大学, 医学(系)研究科(研究院), 講師 (40571659)
• Co-Investigator(Kenkyū-buntansha): 吉田 英樹 京都工芸繊維大学, 応用生物学系, 准教授 (30570600) ; 笠井 高士 京都府立医科大学, 医学(系)研究科(研究院), 准教授 (70516062)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: STXBP1 / αシヌクレイン / ショウジョウバエ / iPS細胞

Outline of Final Research Achievements

We examined the pathology of α-synuclein neurotoxicity in STXBP1 encephalopathy. Microarray analysis using neurons obtained from patient-derived iPS cells revealed changes in the expression of SIAH3 and INPP5F, which have been reported to be associated with Parkinson's disease. We also showed that neurodegeneration observed in the Parkinson's disease model Drosophila was exacerbated by crossing with a mutant of Rop, the Drosophila ortholog of STXBP1. Furthermore, we showed that trehalose supplementation effectively alleviates neuronal phenotypes. These results connect STXBP1 encephalopathy with α-synucleinopathies.

Free Research Field

小児神経学

Academic Significance and Societal Importance of the Research Achievements

発達性てんかん性脳症は多数の原因遺伝子が同定されているが、個別の病態に基づいた治療は存在せず、患者の神経予後は極めて不良である。本研究で発達性てんかん性脳症の代表的な原因遺伝子であるSTXBP1の機能不全とαシヌクレイン神経毒性の関連を示したことは、発達性てんかん性脳症のプレシジョン医療実現に貢献しうると考えられる。