Tubular lysosomes in health and disease

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Abstract Age-dependent degenerative diseases, such as ALS, Alzheimer’s and Parkinson’s disease, are reaching epidemic proportions and no viable treatment options exist to halt or reverse the course of the disease. The lack of disease-modifying treatments is in large part due to our lack of knowledge about the molecular disease pathology. An early hallmark of most degenerative diseases is an accumulation of protein aggregates and damaged organelles, implying that proteostasis defects are an underlying molecular cause of degeneration. Lysosomes are digestive organelles that clear damaged proteins and are also critical regulators of cellular metabolism. Thus, it is not surprising that lysosome impairment is linked to a broad spectrum of degenerative and metabolic diseases. Revealing novel ways to improve or maintain lysosome function in various biological contexts could open promising therapeutic avenues to treat a wide range of metabolic and degenerative diseases. We recently discovered a unique class of degradative tubular lysosomes (TLs) that are conserved in flies, worms and mammals. Significantly, mutation of two genes required for TL maintenance are linked with human degenerative diseases, underscoring the potential biomedical relevance of TLs. Our recent work has demonstrated that TLs are exceptionally digestive, tissue specific and in some cases even stimulus dependent. For example, TLs are stimulated in gut cells during starvation, a major cue that stimulates the autophagy- lysosome system to increase nutrient recycling. We hypothesize that TLs might be deployed under certain conditions when autophagic demand is high. This context dependency also suggests that TLs have the capacity to be stimulated and opens the possibility that TLs could be induced in other tissues where they do not exist naturally, such as neurons. Using worm and fly model systems, we aim to understand fundamental aspects of TL biology in health animals and their connection to human degenerative diseases. Three major research questions we are tackling in my lab include: (1) what are the control mechanisms for starvation- induced TLs in the gut? (2) are TLs functionally distinct from vesicular lysosomes? and (3) is TL dysfunction an underlying cause for age-dependent degenerative diseases? We anticipate that these studies will reveal novel aspects of lysosome biology and might inform strategies to co-opt these mechanisms to boost lysosome function in healthy animals or repair lysosomes in disease states.