Interferon gamma stimulates coordinated changes in LRRK2, GCase, and cathepsin activities in idiopathic and genetic Parkinson's disease monocytes

The immune system is increasingly recognized as playing an important role in the pathogenesis of the neurodegenerative movement disorder Parkinson's disease (PD). In particular, key PD risk genes LRRK2 (which encodes leucine-rich repeat kinase 2) and GBA1 (which encodes glucocerebrosidase) are highly expressed in monocytes and implicated in the regulation of immune inflammatory pathways and lysosomal function. While preclinical studies demonstrate that missense mutations in LRRK2 and GBA1 can modulate the response to inflammatory stimuli, studies in primary immune cells from PD patients harboring these mutations are few. Therefore, peripheral blood mononuclear cells were obtained from idiopathic PD patients, (n = 42), as well as PD patients with GBA1 (n = 15) and LRRK2 (n = 13) mutations, and neurologically normal controls (n = 36). Cells were stimulated with interferon gamma, which strongly induces expression of the LRRK2 protein, and treated with and without the LRRK2 kinase inhibitor MLi-2. Live and fixed cell flow cytometry panels were used to measure the activities of LRRK2 and glucocerebrosidase, as well as cathepsin activity and the expression of the human leukocyte antigen receptor (HLA-DR) in classical, intermediate, and non-classical monocytes. Interferon gamma stimulation had marked effects on LRRK2 levels and phosphorylation of the LRRK2 substrate Rab10, as well as effects on the expression of HLA-DR and cathepsin activity, with some mutation-specific and monocyte-type-specific outcomes. These results help to advance understanding of how risk genes may interact with immune stimuli in the context of PD.