I am developing advanced tools that will open stimulating perspectives in the field of unconventional secretion. I will use these assays to decipher the molecular mechanisms underlying Tau secretion. Targeted approaches will allow to discriminate whether Tau is transported from the cytosol to the extracellular space by direct translocation or through membrane-bound compartments that can derive from autophagic membranes, endosomes and MVBs or secretory lysosomes. Then critical factors at every step of Tau transport should be highlighted thanks to the pooled genome-wide CRISPRi screen. If vesicular compartments are involved, I will reveal how Tau is packed into transport carriers by identifying specific chaperone(s) and transporter(s). I also expect to uncover the source of the membrane for the formation of these transport carriers and if different vesicular intermediates are involved. Identification of the processes of biogenesis, transport and fusion with the membrane of these vesicular intermediates will be of particular interest to characterize the dynamics of these events.
Finally, I expect to identify factors that could be used in the longer-term as potential therapeutic targets for neurodegenerative diseases (NDs), by using Zebrafish models. It will provide a unique opportunity to pinpoint specific genes involved in Tau secretion and the downregulation of which would prevent ND progression.
Taken together, this research program at the crossroad of critical challenges can make important advances into basic cell biology principles. In addition, it is likely that results obtained will yield novel mechanistic insights that would be exploited for biomedical applications. Hence, this project should also have an important impact in the medical, social and economic fields.
Medical applications: The cause of NDs such as AD remains poorly understood, and there are currently no medications to stop or reverse its progression. For this reason, there is an urgent need for innovative treatments and for early biomarkers of the disease. Unravelling mechanisms involved in the trans-cellular spreading of pathological protein species will pave the way for new strategies for its treatment.
Social and economic applications: The incidence of NDs such as Alzheimer’s disease is growing globally, becoming one of the greatest scourges to human health. In 2015, there were approximately 29.8 million people worldwide with Alzheimer’s disease, generating high economical and societal burdens. In addition, currently available treatments are only symptomatic and they are inevitably associated during the progression of the disease to psychosocial and caregiving treatments. Thus, Alzheimer’s disease is among the most financially costly diseases for society in Europe and US. Therefore, any treatment that slows cognitive decline, delays institutionalization or reduces caregivers’ hours will have economic benefits.
