Abstract

Based on the critical role that lysosomes play in cells, the concept behind this project is that a better understanding of lysosomal function will have a major impact on human health, fostering the development of new strategies that will help improve the quality of life of people affected by a variety of diseases, ranging from lysosomal storage diseases (LSDs) to age-related neurodegenerative disorders. The project has the following specific objectives: 1. Identify and characterize genetic modifiers of lysosomal function. Like most genetic diseases, LSDs present a wide range of clinical phenotypes, even in siblings sharing a common mutation. We hypothesize that modifier genes play a role in such phenotypic variability and represent potential new targets for personalized therapeutic approaches. 2. Unravel the mechanism of action of small molecule modifiers of lysosomal function. Recent work revealed several metal imbalances in LSDs. Because drugs that can restore balanced metal levels within cells are available, we will investigate whether therapies that target metal imbalances can be beneficial for treating LSDs. We will also study the cellular and molecular mechanism of action of acetyl-DL-leucine, based on preliminary clinical evidence suggesting that this small molecule can benefit a subset of LSD patients. 3. Investigate the cross-talk between lysosomal function, signalling pathways and gene expression regulation. It has been recently shown that manipulating the expression of defined lysosome-associated genes modulates lysosomal function and that lipids produced in the lysosome move to the nucleus, altering gene expression. Thus, we reason that a better understanding of how lysosomes are reciprocally linked to gene expression has the potential to foster the development of new strategies to treat lysosome-related diseases.