Proteostasis and RNA Binding Proteins in Synaptic Plasticity and in the Pathogenesis of Neuropsychiatric Disorders

Abstract

Decades of research have demonstrated that rapid alterations in protein abundance are required for synaptic plasticity, a cellular correlate for learning and memory. Control of protein abundance, known as proteostasis, is achieved across a complex neuronal morphology that includes a tortuous axon as well as an extensive dendritic arbor supporting thousands of individual synaptic compartments. To regulate the spatiotemporal synthesis of proteins, neurons must efficiently coordinate the transport and metabolism of mRNAs. Among multiple levels of regulation, transacting RNA binding proteins (RBPs) control proteostasis by binding to mRNAs and mediating their transport and translation in response to synaptic activity. In addition to synthesis, protein degradation must be carefully balanced for optimal proteostasis, as deviations resulting in excess or insufficient abundance of key synaptic factors produce pathologies. As such, mutations in components of the proteasomal or translational machinery, including RBPs, have been linked to the pathogenesis of neurological disorders such as Fragile X Syndrome (FXS), Fragile X Tremor Ataxia Syndrome (FXTAS), and Autism Spectrum Disorders (ASD). In this review, we summarize recent scientific findings, highlight ongoing questions, and link basic molecular mechanisms to the pathogenesis of common neuropsychiatric disorders.

Mechanisms underlying the role of DISC1 in synaptic plasticity

“…At least 2550 mRNAs are known to be present in dendrites, and localization of many of these is dependent upon structural elements within their 3′‐UTR (Klein et al . ).…”

“…Dendritic messenger RNA transport. Synaptic activity is partly regulated by localized protein expression, achieved through control of dendritic distribution and translation of mRNAs (Klein et al 2016). At least 2550 mRNAs are known to be present in dendrites, and localization of many of these is dependent upon structural elements within their 3 -UTR (Klein et al 2016).…”

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

“…It is now well accepted that maintaining a fine balance between the synthesis and degradation of RNAs and correct number of mRNAs and RNA-binding proteins is crucial to the proper structure and function of the synapse and, when dysregulated, result in synaptopathies (Grant, 2012) such as FXS and other ASDs (Bagni et al, 2012;Gandal et al, 2018;Klein et al, 2016;Parras et al, 2018). In normal cells, FMRP tightly regulates mRNA stability, transport, and translation.…”

Understanding Neurodevelopmental Disorders: The Promise of Regulatory Variation in the 3′UTRome

“…Genetic variation in MBS sequences has the potential to interfere with miRNA-3 0 UTR interactions (either by destroying or creating MBSs) and thus alter the regulation of protein expression. RBPs can regulate protein expression levels by binding to 3 0 UTR motifs (RBP sites) and either protecting mRNA molecules from degradation or speeding it up (38,39). RBPs can facilitate transport of mRNAs within the cell by binding to 3 0 UTRs, ensuring their localization to the correct subcellular compartment (19).…”