Tuesday, September 26, 2023
9/26/2023
PROJECT SUMMARY Loss-of-function mutations in the progranulin gene (Pgrn haploinsufficiency) cause genetic forms of FTLD with TDP-43 inclusions. The PGRN protein and its bioactive cleavage fragments, the “granulins,” directly modulate activity of the lysosomal protease cathepsin D (CTSD). PGRN traffics to the lysosome as a heterodimer with prosaposin (PSAP). PSAP regulates the levels of sphingolipids, an important class of lipids with roles in intracellular signaling, membrane trafficking and apoptosis. The specific effects of Pgrn haploinsufficiency on protease biology, sphingolipid metabolism and how PGRN and PSAP coordinately regulate protein and lipid homeostasis remain largely unaddressed. We aim to fill these major gaps in knowledge by delineating the complex, downstream effects of PGRN and its cleavage products on lysosomal function. Our long-term goal is to understand how aging and disease- associated lysosomal dysfunction promote neurodegenerative disease. In this application, our overall objective is to determine how Pgrn haploinsufficiency impacts downstream processes such as protease and sphingolipidase activity, TDP-43 and sphingolipid breakdown, and overall protein and lipid homeostasis. Our central hypothesis is that Pgrn haploinsufficiency, via modulation of CTSD activity, confers a “double hit” on protein and lipid metabolism, which impairs both TDP-43 and sphingolipid degradation, ultimately leading to negative downstream consequences on lysosomal function and cellular health. The rationale for our work is that by understanding how PGRN, PSAP and their cleavage products regulate protein and lipid metabolism, we will gain key insights into the mechanisms of neurodegenerative disease pathophysiology. Thus, we propose the following specific aims: 1) Determine how PGRN and its cleavage products affect CTSD-mediated TDP-43 breakdown and protein homeostasis; 2) Understand the impact that PGRN and its cleavage products play on saposin production, sphingolipid levels and lipid homeostasis; 3) Interrogate the effects of Pgrn haploinsuffi- ciency on lysosomal protease and lipidase pathways in humanized models. Upon successful completion of the proposed research, we will have gained understanding of how PGRN impacts downstream lysosomal processes such as protease and sphingolipidase activity, TDP-43 and sphingolipid breakdown, and overall protein and lipid homeostasis. This contribution is significant because it will lead to a comprehensive understanding of the complex, age- and disease-associated events associated with Pgrn haploinsufficiency. This will further translate into better, more rationally targeted approaches to therapy in FTLD-Pgrn and allow better understanding of the basic biology of the lysosome, how proteases and sphingolipidases can be coordinately regulated and how dysfunctional protein and lipid metabolism contribute to FTLD pathogenesis.
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