2022 Fiscal Year Final Research Report

Elucidation of the neural circuitry mechanism causing brain dysfunction in MICPCH syndrome due to X chromosome inactivation.

Research Project

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Project/Area Number	19H03544
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 51030:Pathophysiologic neuroscience-related
Research Institution	Shinshu University
Principal Investigator	Tabuchi Katsuhiko 信州大学, 学術研究院医学系, 教授 (20546767)
Co-Investigator(Kenkyū-buntansha)	森琢磨信州大学, 学術研究院医学系, 助教 (70545798) 付ゆう信州大学, 学術研究院医学系, 助教 (30830301)
Project Period (FY)	2019-04-01 – 2022-03-31
Keywords	CASK / MICPCH症候群 / X染色体不活性化 / 小脳低形成 / 小脳顆粒細胞
Outline of Final Research Achievements	MICPCH syndrome is a neurodevelopmental disorder characterized by cerebellar hypoplasia. It is known to be caused by heterozygosity of the CASK gene on the X chromosome. In this study, we investigated how X chromosome inactivation is involved in cerebellar hypoplasia using mouse models. By crossing CASK knockout mice with Hprt-eGFP mice, in which the EGFP expression cassette is on the X chromosome, we differentiated between CASK positive and negative neurons in the CASK heterozygote knockout brains. We also conducted cerebellar granule cell culture experiments to investigate the molecular mechanism involved in cerebellar hypoplasia. Through these experiments, we found that CASK deficiency caused apoptosis in cerebellar granule cells in a cell-autonomous manner. Additionally, we discovered that the disruption of CASK and Liprin-a2 binding caused by mutations within the CaMK domain of CASK is involved in the molecular mechanism underlying cerebellar hypoplasia in MICPCH syndrome.
Free Research Field	神経生理学
Academic Significance and Societal Importance of the Research Achievements	MICPCH症候群は、日本ではCASK異常症として小児慢性特定疾患に指定されており、重篤な神経発生異常にもかかわらず、治療法が存在しない。特に、小脳低形成は進行性で、徐々に小脳が委縮していくものであり、これを食い止める手段を発見することは急務であるが、現在の所、病態形成メカニズムが不明であるため困難な状況である。本研究で、CASKの異常による小脳顆粒細胞のアポトーシスと、Liprin-a2を介した分子メカニズムが病態形成に関与していることが発見された。このことは、これらの分子を標的とした治療法が開発できる可能性が見えてきたことを意味しており、社会的意義が大きい。