Uncover mechanisms of unconventional secretion of tau using functional CRISPR screens - From basic discoveries to neurodegenerative disease therapeutics

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Most of secreted proteins transit through the endoplasmic reticulum (ER) and the Golgi apparatus. However, eukaryotic cells secrete cytosolic proteins, which do not enter the ER. Proteins that use this “unconventional secretory pathway” include factors with critical functions and deregulation of their transport is associated to a wide range of diseases. Yet, mechanisms of unconventional secretion remain largely uncharacterised. This represents a major gap in our understanding of fundamental mechanisms supporting protein trafficking and secretion. During my previous study, I developed a powerful platform for pooled genome-wide CRISPRi screening with the aim of identifying genes involved in protein transport in mammalian cells. In this proposal, I will use this approach to uncover mechanisms involved in the unconventional secretion of tau. During aging, abnormal accumulation of tau is a common pathological hallmark of neurodegenerative diseases (ND), including Alzheimer’s disease, for which there are no efficient therapeutic to prevent/slow down the pathogenesis. Compelling evidences suggest that tau aggregation occur via its transmission from neuron to neuron. Thus, tau secretion appears to be a pivotal event in promoting ND progression. For these reasons, to understand how tau is secreted is of critical importance. Objectives that will be addressed in this project will be to identify new factors required for tau secretion using a pooled genome-wide CRISPRi screen. Then, by combining biochemical and cellular approaches, as well as the last technologies for imaging, candidate genes will be functionally characterized. Finally, the most relevant factors will be evaluated as potential therapeutic target in zebrafish model of ND. This project will allow uncovering fundamental mechanisms to understand ND progression associated to the unconventional secretion of tau and could ultimately lead to the discovery of effective strategies to develop new therapies.