KGRI Lecture Series: Characterizing roles of Palmitoyl-protein Thioesterase 1 in Developmental Plasticity and CLN1 disease（2022.5.9開催）
2022.04.25慶應義塾大学グローバルリサーチインスティテュート（KGRI）では、国際的な研究・教育交流を図ることを目的として、最先端の研究・教育に携わる方を国内外よりお招きして講演会を開催しています。
今回は、イリノイ大学より吉井聡先生をお招きして、「Characterizing roles of Palmitoyl-protein Thioesterase 1 in Developmental Plasticity and CLN1 disease」と題して講演いただきます。
主 催：グローバルリサーチインスティテュート（KGRI）
日 時：2022年5月9日（月） 11:30－12:30
会 場：慶應義塾大学 信濃町キャンパス 総合医科学研究棟 1階 ラウンジ
開催⽅法︓ハイブリッド形式
参加申込︓こちらよりお申し込みください ＊終了しました。
言 語：英語（同時通訳なし）
講演者：吉井 聡（Assistant Professor, Departments of Anatomy and Cell Biology, Pediatrics and Neurology, College of Medicine, University of Illinois at Chicago）
講演概要：
Infantile neuronal ceroid lipofuscinosis (CLN1) is a devastating neurodegenerative disease that affects children. CLN1 is cause by mutations in the depalmitoylating enzyme palmitoyl-protein thioesterase 1 (PPT1). Protein palmitoylation and depalmitoylation are critical for synaptic function. However, the role of Ppt1-mediated depalmitoylation in neurodevelopmental plasticity and how loss of Ppt1 drives neurodegeneration in CLN1 is unclear. To address these questions, we studied plasticity mechanisms that underlie neural circuit development in the visual cortex of the Ppt1-/- mouse model of CLN1.
In a first set of experiments, the role of Ppt1 in the regulation of N-methyl-D-aspartate (NMDA) receptors was examined. The composition of NMDA receptors shifts during neurodevelopment coincident with the maturation of the visual cortical circuit. We found that loss of Ppt1 leads to a stagnation of this developmental molecular pattern. Specifically, dysregulated synaptic calcium dynamics and left Ppt1-/- neurons vulnerable to excitotoxicity, partly due to hyperpalmitoylation of the immature NMDA receptor subunit GluN2B.
In a second line of experimentation, the role of Ppt1 in the synaptic scaling of ɑ-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors was examined. Ppt1-/- neurons demonstrated exaggerated synaptic upscaling of calcium-permeable AMPA receptors in vitro and in vivo. A postsynaptic scaffold implicated in synaptic scaling, A-kinase anchor protein 5 (Akap5), was over-palmitoylated in Ppt1-/- neurons. Further, this pathway linked for the first time dysregulated synaptic calcium to a neuroinflammatory cascade in CLN1.
Together, these findings emphasize a vital role for PPT1-mediated depalmitoylation in synaptic plasticity that underlies circuit formation and function in the developing nervous system.
本件に関するお問い合わせ
医学部生理学教室（内線：62613）
