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The Effective Rescue of Lysosomal Dysfunction in GBA Neural Progenitor Cells with KM-819

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Gaucher’s Disease is associated with mutation(s) in the GBA gene that results in the loss of the lysosomal enzyme glucocerebrosidase (GCase). It has been well established that GBA patients show a significant increase in incidence of Parkinson’s Disease (PD). Thus, targeting and effectively rescuing lysosomal functions presents as an attractive strategy for developing therapies for GD-PD. My research is to define 1) if lysosomal dysfunction exists in Neural Progenitor Cells (NPC) derived from human induced pluripotent stem cells (hiPSC) from GBA patients as well as from healthy control (HC) patients and 2) if an autophagy-enhancing small molecule (KM-819) can rescue lysosomal dysfunction in GBA cells. Based on previously published literature, I hypothesize that KM-819 increases/rescues lysosomes by enhancing autophagy. I carried out western blots and found that LAMP2, a lysosomal membrane protein, along with ATG3 and ATG5, both autophagic proteins, were dramatically increased in GBA cells after treatment, providing initial support for my hypothesis. I then treated the cells with either vehicle or KM-819 and used LysoTrackers to assess the lysosomal dynamics by live cell imaging. The results show that treating GBA cells with 1 M KM-819 for 24 hours effectively restored the lysosomal size and motility, making it indistinguishable from the HC cells. An interesting finding was that the KM-819 treatment only affected (increased) lysosomes in GBA cells but not HC cells. Thus, these results lend strong support for my hypothesis. If further validated, KM-819 will be a promising drug for treating Parkinson’s Disease associated with GBA mutations.

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This item is under embargo until December 21, 2023.