Friday, March 14, 2025
3/14/2025
Aging-associated diseases are an increasing socio-economic burden despite efforts to improve healthspan. Pathologies that cause degeneration of the nervous system are particularly devastating, and in many cases are associated with decline in proteostasis and lysosomal malfunction. Prime examples are Parkinson and Alzheimer’s disease that are characterized by accumulation of insoluble protein aggregates that lead to neuronal decay. Lysosomal degradation of cytoplasmic components depends on proper transport of hydrolases from the Golgi to lysosomes where they encounter the acidic environment necessary for their activation. Lysosomes are also important regulatory hubs that integrate nutritional signals and participate in lipid metabolism, and these diseases are associated with alterations in lysosomal pH and accumulation of lipids, particularly cholesterol in the lysosome. We have recently characterized Drosophila Lamp1, a bona fide homolog of the mammalian LAMP1/2 proteins with partially redundant roles in autophagy and cholesterol assimilation. Drosophila Lamp1 localizes to late endosomes and lysosomes and is, in contrast to Lamp1/2, not required for development, autophagy, or viability; however, males have a reduced mean lifespan. Critically, Lamp1 deficiency results in an increase in the number of acidic organelles in the fat body, strongly suggesting defects in the regulation of the pH of the endolysosomal system. Furthermore, Lamp1 mutant larvae have elevated levels of sterols and diacylglycerols, indicating functions of Lamp1 in lipid transport beyond sterols, that we are in the unique possibility to assess in the absence of confounding autophagy defects. This proposal will identify the connection between Lamp1 function, endolysosomal acidification, and lipid metabolism, and investigate how these processes are connected to neurological disorders. Because altered endolysosomal regulation contributes to many aging- related diseases, our research will significantly advance our understanding of how dysfunction of endolysosomal system underlies disease, ultimately leading to the development of novel treatment strategies to improve healthspan.
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