Arc Requires PSD95 for Assembly into Postsynaptic Complexes Involved with Neural Dysfunction and Intelligence

Abstract

SummaryArc is an activity-regulated neuronal protein, but little is known about its interactions, assembly into multiprotein complexes, and role in human disease and cognition. We applied an integrated proteomic and genetic strategy by targeting a tandem affinity purification (TAP) tag and Venus fluorescent protein into the endogenous Arc gene in mice. This allowed biochemical and proteomic characterization of native complexes in wild-type and knockout mice. We identified many Arc-interacting proteins, of which PSD95 was the most abundant. PSD95 was essential for Arc assembly into 1.5-MDa complexes and activity-dependent recruitment to excitatory synapses. Integrating human genetic data with proteomic data showed that Arc-PSD95 complexes are enriched in schizophrenia, intellectual disability, autism, and epilepsy mutations and normal variants in intelligence. We propose that Arc-PSD95 postsynaptic complexes potentially affect human cognitive function.

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways

“…On the other hand, MAGMA competitive gene-set analysis revealed a significant enrichment of discordant genes for functions including synaptic transmission and the postsynaptic density, as well as membrane depolarization and voltage-gated cation channel activity. While these processes have been commonly associated with both schizophrenia 33,35 and cognitive phenotypes [22][23][24][90][91][92] , our study is the first to demonstrate that these synaptic mechanisms operate in a surprising manner: the same synaptic functions that increase risk for schizophrenia also serve to enhance educational attainment.…”

Large-scale proteomic analysis of human prefrontal cortex identifies proteins associated with cognitive trajectory in advanced age

“…Remarkably, the top protein of this 38-protein list is DLG4, also known as PSD95, which is one of the most abundant scaffold proteins at the excitatory brain synapses and known to affect brain development, neuronal plasticity, memory and learning, and overall cognitive function [41][42][43] . We asked whether proteins known to interact with PSD95, i.e.…”

Structures of virus-like capsids formed by the Drosophila neuronal Arc proteins

“…Arc protein regulates synaptic function via trafficking of AMPA-type glutamate receptors Shepherd et al, 2006) and interacts with proteins at the synapse including PSD95 (Fernandez et al, 2017;Okuno et al, 2012), the transmembrane AMPAR regulatory protein g2 (TARPg2) (Jackson and Nicoll, 2011), Ca 2+/ calmodulin dependent kinase (CaMKII) (Okuno et al, 2012) and several proteins involved in clathrin-dependent endocytosis DaSilva et al, 2016). Thus, elucidating the structure and function of Arc will shed light on fundamental mechanisms of cognition.…”