Abstract 2921 Lysosome-acidifying nanoparticles rescue A30P α-synuclein induced neuronal death in cellular and animal models of Parkinson's disease

During brain development, neuronal connections strengthen and weaken in response to a changing environment.This is our understanding of synaptic plasticity and its importance in learning and memory.Changes in gene expression in response to synaptic and neuronal activity is known as excitation-transcription coupling (E-TC).In the field, E-TC is suggested to be a mechanism underlying learning and memory.How synaptic activity is relayed to the nucleus where transcriptional changes occur is not well understood.We hypothesize that intrinsically disordered regions (IDRs) of post-synaptic channels play a role in driving phase separation at the post-synaptic density (PSD).These phase-separated biocondensates mediate signaling to the nucleus and regulate synapse-nuclear signaling.To investigate this hypothesis, we will examine the role of IDRs in MAPK-ERK signaling, a cascade necessary for the transcription of rapid immediate early genes (rIEGs), such as Arc.To test this, we fused the CTD of NR2B to Channelrhodopsin and optogenetically controlled Ca2+ entry to facilitate MAPK-ERK signaling.Our results suggest that the intrinsically disordered CTD of the NMDA receptor could play an important role in MAPK-ERK signaling.Understanding how IDRs of different channels regulate synapse-nuclear signaling will help provide deeper insights of synaptic mechanisms and potential new therapeutic interventions for synapse-related diseases like neurodevelopmental disorders.