Perturbed proteostasis in autism spectrum disorders

Abstract

Dynamic changes in synaptic strength rely on de novo protein synthesis and protein degradation by the ubiquitin proteasome system (UPS). Disruption of either of these cellular processes will result in significant impairments in synaptic plasticity and memory formation. Mutations in several genes encoding regulators of mRNA translation and members of the UPS have been associated with an increased risk for the development of autism spectrum disorders. It is possible that these mutations result in a similar imbalance in protein homeostasis (proteostasis) at the synapse. This review will summarize recent work investigating the role of the UPS in synaptic plasticity at glutamatergic synapses, and propose that dysfunctional proteostasis is a common consequence of several genetic mutations linked to autism spectrum disorders. Dynamic changes in synaptic strength rely on de novo protein synthesis and protein degradation by the ubiquitin proteasome system (UPS). Disruption of either of these cellular processes will result in significant impairments in synaptic plasticity and memory formation. Mutations in several genes encoding regulators of mRNA translation (i.e. FMR1) and protein degradation (i.e. UBE3A) have been associated with an increased risk for autism spectrum disorders and intellectual disability (ASD/ID). These mutations similarly disrupt protein homeostasis (proteostasis). Compensatory changes that reset the rate of proteostasis may contribute to the neurological symptoms of ASD/ID. This review summarizes recent work investigating the role of the UPS in synaptic plasticity at glutamatergic synapses, and proposes that dysfunctional proteostasis is a common consequence of several genetic mutations linked to ASD. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases".

Keywords: ASD/ID; autism; proteasome; synaptic plasticity; translation; ubiquitin.

Figure 1

Dysregulation of protein synthesis or degradation results in unbalanced proteostasis. (a) Mutations in several genes that regulate mRNA translation and ubiquitin proteasome system function have been implicated in ASD/ID (see Tables 1, 2). This includes regulators of translation control signaling pathways (TSC1/2, NF1, PTEN, SYNGAP1, PTPN11, HRAS), protein synthesis regulators (FMR1, CYFIP1, EIF4E, RBMS3, RPL10, RPSS6KA2,3), E3 ubiquitin ligases (UBE3A,B,C, CULLIN3,7, PARK2, FBXO40, RFWD2, HERC2, HECW2, HUWE1), de‐ubiquitinases (USP7, USP45, USP9Y), and the proteasome protein PSMD10. The proteins encoded by these genes collectively contribute to the proteostasis involved in synaptic plasticity. (b) The pathogenic excess in synaptic protein synthesis observed in animal models of ASD/ID (i.e. FMR1,SYNGAP1, and CYFIP1) may lead to a homeostatic increase in UPS function. Similarly, mutations in E3 ligases, such as Ube3A, that decrease UPS function may result in a compensatory decrease in protein synthesis. In both cases, the imbalance in proteostasis would lead to a change in the composition of new versus old plasticity related proteins (PrPs) in the synaptic proteome without necessarily affecting overall protein levels.