Investigating proteostasis in development and disease using iPSC neurons with MAPT mutations linked to FTD

Proteostasis is the tightly controlled integration of multiple cellular processes to regulate thesynthesis and degradation of intracellular and extracellular proteins. The activity of two key proteostasis pathways, the ubiquitin proteasome system (UPS) and autophagy, is high in early development, where the rapid synthesis and turnover of morphogens is critical to appropriate neuronal patterning and the development of proper connectivity. Further, a breakdown of proteostasis is implicated in neurodegenerative diseases, the majority of which are characterised by the accumulation of pathological protein aggregates. Hyperphosphorylated, insoluble aggregates of the microtubule associated-protein tau characterise a number of neurodegenerative diseases including Alzheimer's Disease, and mutations in the tau gene (MAPT) are causative of FTD, demonstrating a causal link between tau dysfunction and neurodegeneration. Pathological tau is degraded both by the UPS and autophagy, and pathological tau has been shown to directly
bind to and inhibit the proteasome. Enhancing proteostatic activity is able to ameliorate disease phenotypes in rodent models of tauopathy; therefore promoting the turnover of pathological tau species may be an attractive therapeutic target.

iPSC-neurons present a unique opportunity to investigate the link between proteostasis and protein aggregation in disease in a physiologically relevant, patient model. Based on transcriptomics, iPSC-neurons are through to largely resemble foetal neurons. Many of the features associated with the development of tau pathology, such as high levels of phosphorylation, are also present in foetal neurons. iPSC-neurons with MAPT mutations do not develop tau aggregates, and this raises the question of why foetal neurons appear to be resistant to the development of tau pathology?. We hypothesise this is due to high activity levels of the proteostasis network during early development. In this project we will investigate the proteostasis capabilities of iPSC-neurons through neuronal development, determine whether mutations in MAPT lead to impaired proteostasis in iPSC-neurons and asses whether manipulation of proteostasis can induce tau pathology.