Molecular Pathogenesis of the abnormal spine morphology and 5-HTR complex induced by ASD-related mutated Mupp1

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K06744
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Tokyo Medical University
• Principal Investigator: MOMOI TAKASHI 東京医科大学, 医学部, 客員教授 (40143507)
• Co-Investigator(Kenkyū-buntansha): 神保 恵理子 (藤田恵理子) 自治医科大学, 医学部, 講師 (20291651) ; 林 由起子 東京医科大学, 医学部, 主任教授 (50238135)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: 自閉症スペクトラム障害 / MUPP1 / CADM1 / スパイン形成

Outline of Final Research Achievements

Caspr2 has a PDZ binding domain at C-terminal region and forms a complex with receptors via interaction with Multiple PDZ domain protein 1 (Mupp1). However, little is known about the impaired Caspr-2-Mupp1-receptor complex related to the pathogenesis of ASD. Caspr2 and GPR37 mainly interacted with PDZ3 and PDZ11 domains of Mupp1 via their C-terminal PDZ binding domains, respectively. In the present study, we found two missense mutations in Mupp1 gene of the ASD patients and investigated the density and morphology of PSD95-positive dendritic spines and protrusions in cultured hippocampal neurons overexpressing the mutated Mupp1. Compared to the Mupp1, mutated Mupp1 significantly reduced the density of PSD95-positive dendritic spines and decreased the width of dendritic spines. Thus, ASD-related Mupp1 missense mutations have influence on the dendritic spine morphogenesis, causing the pathogenesis of ASD.

Free Research Field

神経分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究は、Caspr2(Cadm1)-Mupp1-receptor複合体に関して、自閉症スペクトラム障害(ASD)関連の変異とスパイン形成との関連を明らかにした点に学術的意義がある。また、本研究成果は、ASDの分子病態の解明に役立つとともに、ASDの治療法の開発に役立つことが期待される点に社会的意義がある。