KGRI Lecture Series: Characterizing roles of Palmitoyl-protein Thioesterase 1 in Developmental Plasticity and CLN1 disease (May 9, 2022)2022.04.25
The Keio University Global Research Institute (KGRI) aims to promote international research and educational exchange and invites those working in the forefront of research and education in Japan and overseas to give lectures.
This time, Professor Akira Yoshii from College of Medicine; Departments of Anatomy and Cell Biology, Pediatrics and Neurology, University of Illinois at Chicago, will give a lecture titled "Characterizing roles of Palmitoyl-protein Thioesterase 1 in Developmental Plasticity and CLN1 disease"
Host: Keio University Global Research Institute (KGRI)
Date & Time: Monday, May 9, 2022 11:30-12:30
Venue: 1F Lounge, Center for Integrated Medical Research, Shinanomachi Campus, Keio University
Registration: Click here to register *This event has ended.
Speaker: Akira Yoshii, M.D. Ph.D. (Assistant Professor, University of Illinois at Chicago; College of Medicine; Departments of Anatomy and Cell Biology, Pediatrics and Neurology)
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.
For inquiries about this event:
School of Medicine, Department of Physiology (ext. 62613)