Lysosomal calcium signalling and autophagy

Lysosomal calcium signalling and autophagy
We contributed to the discovery that lysosomal biogenesis and autophagy are transcriptionally regulated by the transcription factor EB (TFEB). Upon nutrient starvation mTOR signalling is inhibited while TFEB and its network of target genes are activated. We discovered that lysosomal Ca2+ release through the non-selective cation channel TRPML1 plays a major role in lysosomal adaptation to starvation by activating the Ca2+-dependent phosphatase calcineurin, that de-phosphorylates and activates TFEB (Medina DL, et al, 2015). Focusing in TRPML1, we also found that its activation plays a major role in the initiation of autophagy by promoting autophagosome biogenesis through the AMPK/VPS34 pathway. Our laboratory is now focused on; 1) the study of TRPML1 activation upon nutrient deprivation; 2) the role of TRPML1 and lysosomal calcium signalling in autophagy, and 3) the identification of TRPML1 interactors involved on lysosomal function and signalling. To study these important aspects of lysosomal biology we are utilizing molecular and cellular biology, High Content Imaging, and OMIC approaches.
Repurposing approach to cure lysosomal storage disorders
We contributed to the discovery that TFEB over-expression can promote cellular clearance in different lysosomal storage disorders (LSDs) by inducing lysosomal exocytosis, a process that requires TRPML1-dependent Ca2+ release (Medina DL, et al, 2011). This seminal finding was subsequently independently confirmed by many other labs, suggesting that either TRPML1 or TFEB may represent novel therapeutic targets for the identification of compounds modulating its clearance activity. Over the last few years, we have developed cell-based high content imaging screening approaches to identify compounds able to induce the TFEB pathway in cellular models of LSDs. In particular, we have focused on the repurposing of FDA-approved drugs to tackle Batten Diseases, Mucopolysaccharidosis and Mucolipidosis type IV. The identification of FDA drugs correcting LSDs may significantly reduce the costs and time associated with clinical translation.

The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from January 2022 until last budget year, calculated based on the size of the research group.