LRRK2 activity regulates Rab phosphorylation, BMP and glycosphingolipids at the lysosome

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 that LRRK2 regulates the secretion of BMP- and GSL-containing vesicles and can also modulate BMP levels as a secondary consequence of its effects on GCase activity.  


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Thursday, July 28, 2022 - 13:00 ET
Anastasia Henry (Denali Therapeutics)