Elucidation of the phosphorylation mechanism of the Rett syndrome-causing gene CDKL5 during neuronal differentiation

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K15751
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 43030:Functional biochemistry-related
• Research Institution: The University of Tokushima (2021-2022); Ritsumeikan University (2020)
• Principal Investigator: KATAYAMA Syouichi 徳島大学, 大学院医歯薬学研究部(薬学域), 助教 (60779049)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: CDKL5 / CDKL5欠損症 / 神経細胞分化 / シグナル伝達 / P19細胞 / Phos-tag SDS-PAGE / タンパク質リン酸化 / Rett症候群

Outline of Final Research Achievements

Cyclin-dependent kinase-like 5 (CDKL5) is a serine/threonine protein kinase. Mutations in the CDKL5 gene cause psychiatric and neurological disorders associated with epileptic seizures early after birth. This disorder has historically been recognized as a subtype of Rett syndrome, but recently identified as a unique disorder called “CDKL5 deficiency disorder.” In this study, we worked on molecular level analysis to elucidate the onset mechanism of CDKL5 deficiency. As a result, we clarified that the phosphorylation state of CDKL5 changes during neuronal differentiation. Moreover, we identified the kinase responsible for this phosphorylation.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

CDKL5欠損症を発症させるその分子機序の解明には、CDKL5がどのような分子と相互作用するかを見出すことが必須の課題となる。しかしながら、CDKL5がリン酸化する基質やCDKL5の機能を制御するタンパク質の情報はほとんど明らかにされていないのが現状であった。研究代表者が見出したCDKL5の神経細胞分化過程におけるリン酸化状態の変動は、CDKL5の制御機構と神経細胞分化の関係を明らかにするための重要な知見であり、今後CDKL5欠損症の発症機構を解明するための手がかりとなる。