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Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2021)

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 (Compound A) can rescue lysosomal dysfunction in GBA cells. Basedon previously published literature, I hypothesize that Compound A 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 Compound A and used LysoTrackers to assess the lysosomal dynamics by live cell imaging. The results show that treating GBA cells with 1 μM Compound A for 24 hours effectively restored the lysosomal size and motility, making it indistinguishable from the HC cells. An interesting finding was that the Compound A treatment only affected (increased) lysosomes in GBA cells but not HC cells. Thus, these results lend strong support for my hypothesis. If further validated, Compound A will be a promising drug for treating Parkinson’s Disease associated with GBA mutations.

    Cover page: The Effective Rescue of Lysosomal Dysfunction in GBA Neural Progenitor Cells with Compound A
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2022)
    Rab7 GTPase regulates mitochondrial morphology and function. Missense mutation(s) of Rab7 underlies the pathogenesis of Charcot Marie Tooth 2B (CMT2B) peripheral neuropathy. Herein, we investigate how mitochondrial morphology and function are impacted by the CMT2B associated Rab7V162M mutation. In contrast to recent studies of using heterologous overexpression systems, our results demonstrate significant mitochondrial fragmentation in both human CMT2B patient fibroblasts and CMT2B embryonic fibroblasts (MEFs). Primary cultured E18 dorsal root ganglion (DRG) sensory neurons also show mitochondrial fragmentation and altered axonal mitochondrial movement. In addition, we demonstrate that inhibitors to either the mitochondrial fission protein Drp1 or to the nucleotide binding to Rab7 normalize the mitochondrial deficits in both MEFs and E18 cultured DRG neurons. Our study reveals, for the first time, that expression of CMT2B Rab7 mutation at the physiological level enhances Drp1 activity to promote mitochondrial fission, potentially underlying selective vulnerability of peripheral sensory neurons in CMT2B pathogenesis.
      Cover page: Mitochondria dysfunction in Charcot Marie Tooth 2B Peripheral Sensory Neuropathy.
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