Investigations into the mechanisms of neuronal proteostasis

Abstract

Protein homeostasis or proteostasis is essential for efficient synaptic transmission, as well as learning and memory. Many neuronal diseases arise from pathologic alterations in the rates of essential cellular processes such as transcription, translation, transport, and degradation of both mRNA and protein products. The complex morphologies of neurons present the unique challenge of coordinating proteostasis across extensive axonal and dendritic arbors which support thousands of individual biochemical compartments known as dendritic spines.;Proteostais arises from the spatially, and temporally, coordinated activities of the cellular machinery. In the case of transcription and translation mRNA must be made and delivered to the correct dendritic regions where it may remain translationally dormant until receipt of activating synaptic activity. My thesis work has focused on how the RNA-binding protein Sam68 regulates mRNA transport and translation to ensure normal synaptic function. I have also examined how translation and degradation coordinate dendritic protein abundance during long-term plasticity. I hope that these pathways I have elucidated shed light onto how neurons coordinate multiple systems to achieve proteostasis of the massively complex neuronal proteome.