The ubiquitin proteasome system as a regulator of neuronal function

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The accumulation of damaged and misfolded proteins is toxic to cells and is believed to play a major role in neuronal ageing and neurodegenerative disorders such as Alzheimer's disease and Amyotrophic Lateral Sclerosis. In order to maintain protein homeostasis cells have protein degradation pathways which serve to repair or remove damaged proteins. The targeting of damaged proteins for degradation is primarily mediated by the Ubiquitin Proteasome System (UPS). Importantly, specific isoforms of the E3 ligases, which comprise a key part of the UPS, are known to localise within neurons. The loss of E3 ligase efficacy and the resultant perturbation of protein homeostasis is believed to contribute to neuronal ageing and neurodegeneration. Intriguingly, there is mounting evidence that these proteins also serve as key modulators of neuronal function in the healthy nervous system. For example, the UPS has been shown to regulate the grown of axons, the formation of synapses and the release of neurotransmitter. However, we know relatively about how E3 ligases influence vertebrate neurons in vivo. This project will use zebrafish, a powerful vertebrate model for in vivo neuroscience research, to understand how molecular and pharmacological perturbation of the UPS influences the physiology function, morphology, connectivity and output of neural tissue.