Peripheral ß-glucocerebrosidase enzyme activity and lipidomics in ß-glucocerebrosidase (GBA1) mutation Parkinson disease (P2.149)

OBJECTIVE: To determine whether peripheral s-glucocerebrosidase (GCase) enzyme activity and lipid levels are potential markers for GBA1 mutation Parkinson disease (GBA-PD). BACKGROUND: Mutations in GBA1, which encodes lysosomal enzyme GCase, lead to increased glycolipids in biallelic Gaucher disease and increased risk of Parkinson disease (PD) in the heterozygous form. The relationship between GCase activity, lipid levels and clinical outcomes could identify pharmacodynamic markers in GBA-PD and elucidate disease etiology. DESIGN/METHODS: Sera for high level lipidomics and dried blood spots (DBS) for GCase activity were collected from 15 PD with one of the 8 major Ashkenazi Jewish GBA1 mutations (GBA-PD), 13 non-GBA idiopathic PD (IPD) and 5 non-GBA, non-PD controls. Major blood sphingolipids built on C18:1 and C18:0 sphingoid bases, sphingoid base phosphates, and molecular species of ceramide, hexosylceramides, and lactosylceramides were analyzed by tandem HPLC-Mass spectrometry (MS/MS). GCase was assessed from DBS using tandem mass spectroscopy. GBA-PD, IPD and controls were compared using Mann-Whitney. Generalized linear models were also tested. RESULTS: The mean levels of prominent brain lipids C18:1 hexosylceramide, C18 ceramide, and sphingosine were increased in GBA-PD (3.4±5.3, 6.4±2.8, 3.4±2.9 pmol/mL) compared to controls (0.2±0.1, 3.8±0.6, 0.8±0.3) (p=0.02, p=0.01, p<0.01) and IPD (0.2±0.04, 4.3±1.3, 1.5±1.0) (p=0.02, p=0.01, p<0.01). GCase activity was significantly decreased in GBA-PD (3.49±2.81 μmol/L/h) compared to controls (6.13±1.26) (p=0.04) and IPD (7.05±4.94) (p=0.03). While overall IPD did not differ from controls, a subset had glycolipid levels and GCase activity in abnormal ranges. CONCLUSIONS: Increased lipid levels and decreased GCase activity in GBA-PD compared to IPD and controls suggest disruption of the GCase enzymatic pathway in GBA-PD, and indicate potential markers. Increases specifically of prominent brain lipids in the GCase pathway further support the possibility of shared pathophysiology between Gaucher disease, GBA-PD, and a subset of IPD. Study Supported by: NIH K02NS073836, Marcled Foundation, Bigglesworth Foundation Disclosure: Dr. Glickman has nothing to disclose. Dr. Bodamer has nothing to disclose. Dr. Johnson has nothing to disclose. Dr. Nichols has nothing to disclose. Dr. Pullman has nothing to disclose. Dr. Ortega has nothing to disclose. Dr. Johannes has nothing to disclose. Dr. Raymond has nothing to disclose. Dr. Ozelius has nothing to disclose., Dr. Bielawski has nothing to disclose. Dr. Bressman has nothing to disclose. Dr. Obeid has nothing to disclose. Dr. Hannun has nothing to disclose. Dr. Saunders-Pullman has nothing to disclose.