Lysosomal calcium signalling and autophagy

We have recently shown that lysosomal Ca2+ release through the non-selective cation channel TRPML1 plays a major role in lysosomal adaptation to starvation.  Mutations in TRPML1 cause mucolipidosis type IV (MLIV), a severe lysosomal storage disorder characterized by psychomotor retardation and achlorhydria. The symptoms typically manifest in the first years of life and there is still no cure to treat patients affected by this disorder. At the cellular level MLIV-affected cells show accumulation of aberrant lysosomes filled with auto-fluorescent lipid material, including cholesterol. In addition, lysosomal dysfunction results in a partial block of autophagy while that TRPML1 over-expression promotes autophagy flux. Interestingly, accumulation of lipids as well as disturbed lysosomal Ca2+ homeostasis have been described in different LSDs and in some cases have been proposed to involve the lysosomal Ca2+ channel TRPML1, suggesting that TRPML1 impairment may be part of the pathogenic mechanisms in many other LSDs. 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. The final goal of our research is the discovery of compounds activating TRPML1-dependent pathways, and use these compounds to treat human diseases characterized by lysosomal/autophagic dysfunction.

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 July 2016 until last budget year, calculated based on the size of the research group.