LRRK2 kinase activity regulates Parkinson's disease-relevant lipids at the lysosome.

ABSTRACT:

Background

Pathogenic variants in LRRK2 lead to increased kinase activity, and LRRK2 kinase inhibition is being explored in clinical studies as a therapeutic approach for Parkinson's Disease (PD). LRRK2 inhibitors reduce urine levels of bis(monoacylglycerol)phosphate (BMP), a key endolysosomal lipid involved in glycosphingolipid (GSL) catabolism, in preclinical models and clinical subjects. However, how LRRK2 regulates BMP and its significance with respect to lysosomal dysfunction in PD are poorly defined.

Methods

Using a combination of genetic and pharmacological approaches to modulate LRRK2 kinase activity, we explored the mechanisms by which LRRK2 can regulate the levels of BMP and PD-relevant GSLs across cellular models, including iPSC-derived microglia, and in tissues a

SUBMITTER: Maloney MT 

PROVIDER: S-EPMC12330094 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature