Decreased Cholesterol in Olfactory Mucosal Cells from Parkinson's Disease patients with Leucine-Rich Repeat Kinase 2 Mutations

We have previously reported that neuromelanin-associated cholesterol is reduced in the substantia nigra in Parkinson’s disease (PD).Further, cholesterol biosynthesis is reported to be reduced in fibroblasts from patients with PD. Together these data suggest a change in cholesterol homeostasis in PD. To examine this hypothesis, olfactory mucosal cells were biopsied and cultured from six cases of idiopathic PD (iPD) patients, four PD patients with leucine-rich repeat kinase 2 (LRRK2) mutations (two A1442P and two G2019S mutations) and 10 normal controls. Cellular cholesterol levels were measured by reverse phase high performance liquid chromatography and the activity and amount of the rate-limiting cholesterol biosynthetic enzyme, 3-hydroxy-3-methyl-glutaryl-CoAreductase (HMG CoA-R), were measured by metabolic radio labelling and Western blotting, respectively. Cells from PD patients withLRRK2 mutations demonstrated significantly lower cholesterol levels compared with iPD (37% reduction, p = 0.02) and controls (38% reduction, p = 0.005). HMG CoA-R activity and protein were, however, unchanged in these cells. No difference was found in the cholesterol level in cells from iPD cases compared with controls, nor did there appear to be any effect of LRRK2 mutation type on cholesterol levels. Our findings suggest that LRRK2 might play a role in cholesterol-associated pathways.