The role of LRRK2 in enteric neurogenesis and the pathogenesis of Parkinson's disease

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07764
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Kitasato University
• Principal Investigator: Tatsunori Maekawa 北里大学, 医療衛生学部, 講師 (30647673)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: パーキンソン病 / 腸管神経系

Outline of Final Research Achievements

Parkinson's disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons in the substantia nigra pars compacta. The aim of this study is to elucidate the role of LRRK2 in the enteric nervous system (ENS) and the pathogenesis in the ENS of PD. We revealed that LRRK2 is predominantly expressed in enteric glial cells rather than neurons. Furthermore, the number of bi-phenotypic cells which has both phenotypes of neuron and the glial cells was increased in LRRK2-knockout mice. We also revealed that LRRK2 regulates enteric neurogenesis through the phosphorylation of CREB. In the ENS of KO mice, the protein level of alpha-synuclein was elevated which might become a trigger of the onset of PD.

Free Research Field

腸管神経

Academic Significance and Societal Importance of the Research Achievements

本研究により、LRRK2による腸管神経障害のメカニズムが明らかになれば、LRRK2を標的とした治療薬開発に重要な知見を与えることができる。また、腸が生検可能な臓器であること、運動症状よりも腸症状が先行することから、発症前診断への発展も期待できる。早期診断と早期治療介入により発症時期を遅らせることができれば、介護・医療負担を軽減できるだけでなく、健康寿命の延伸も期待することができる。加速化する高齢化社会の中で本研究の持つ意義は大きい。