The most frequent missense mutations in familial Parkinson’s disease (PD) occur in the highly conserved LRRK2/PARK8 gene with G2019S mutation. We previously established a fly model of PD carrying the LRRK2-G2019S mutation that exhibited the parkinsonism-like phenotypes. An herbal medicine, Gastrodia elata Blume (GE), has been reported to have neuroprotective effects in toxin-induced PD models. However, the underpinning molecular mechanisms of GE beneficiary to G2019S-induced PD remain unclear.
LRRK2 Central Seminar Series | Past Seminars
LRRK2 activity regulates the phosphorylation of a subset of Rab proteins, and Rab phosphorylation on lysosomes can be modulated in response to variants in PD-linked proteins and lysosomal damage. In addition to sensing lysosomal damage, LRRK2 can also promote lysosomal dysfunction, leading to reduced GCase activity and alterations in BMP. Using cellular and rodent models and PD patient samples, we explored the mechanisms by which LRRK2 regulates BMP and its functional significance with respect to GSL metabolism and disease. We show tha
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Our laboratory is focused on understanding the dynamics of organelle motility along the cellular cytoskeleton, driven by molecular motors: cytoplasmic dynein, kinesins, and myosins. The active transport of membrane-bound organelles is required for intracellular biosynthetic and endocytic trafficking in most eukaryotic cells. However, the highly polarized morphology of neurons, with axons that can extend over distances of up to one meter, make these cells uniquely dependent on motor-driven transport.
Mutations in Leucine-rich repeat kinase 2 (LRRK2) have been linked most infamously to Parkinson’s disease but also to a host of chronic inflammatory diseases, cancer, and susceptibility to infection; however, the underlying mechanisms through which LRRK2 mutations promote disease are unknown. We discovered that macrophages harboring the common human mutation Lrrk2G2019S are more prone to regulated cell death in response to both Mycobacterium tuberculosis (Mtb) infection and canonical inflammasome activation.