LRRK2 Kinase Activity Regulates Parkinson's Disease-Relevant Lipids at the Lysosome

Lysosomal dysfunction is a hallmark of Parkinson's disease (PD), and variants in several PD-associated genes, including LRRK2, perturb lysosomal homeostasis. Based on this, LRRK2 kinase inhibition is being explored as a therapeutic approach for the treatment of PD. LRRK2 inhibitors reduce levels of BMP, an endolysosomal lipid involved in glycosphingolipid (GSL) catabolism, in urine from preclinical models and clinical subjects, however, the mechanisms by which LRRK2 regulates BMP and the functional significance of this change to disease are undefined. We establish that LRRK2 regulates secretion of BMP- and GSL-containing vesicles from kidney into urine and modulates BMP and GSL levels in the brain. BMP accumulates within lysosomes as a secondary response to LRRK2's effects on the activity of glucocerebrosidase (GCase), a PD-linked enzyme involved in GSL catabolism. Alterations in BMP and GCase substrate turnover are observed in CSF from LRRK2-PD patients, highlighting the relevance of LRRK2-dependent lysosomal dysfunction in disease. ### Competing Interest Statement The authors declare the following competing interests: Michael T. Maloney, Xiang Wang, Rajarshi Ghosh, Shan V. Andrews, Romeo Maciuca, Shababa T. Masoud, John Chen, Chi-Lu Chiu, Sonnet S. Davis, Audrey Cheuk-Nga Ho, Hoang N. Nguyen, Nicholas E. Propson, Oliver B. Davis, Gilbert Di Paolo, Anthony A Estrada, Javier de Vicente, Joseph W. Lewcock, Annie Arguello, Jung H. Suh, Sarah Huntwork-Rodriguez, and Anastasia G. Henry are employees of Denali Therapeutics.