Abstract
Missense mutations in glucocerebrosidase (GBA1) that impair the activity of the encoded lysosomal lipid metabolism enzyme (GCase) are linked to an increased risk of Parkinson’s disease. However, reduced GCase activity is also found in brain tissue from Parkinson’s disease patients without GBA1 mutations, implicating GCase dysfunction in the more common idiopathic form of Parkinson’s disease. GCase is very highly expressed in monocytes, and thus we measured GCase activity in blood samples from recently diagnosed Parkinson’s disease patients. Flow cytometry and immunoblotting assays were used to measure levels of GCase activity and protein in monocytes and lymphocytes from patients with Parkinson’s disease (n = 48) and matched controls (n = 44). Gene sequencing was performed to screen participants for GBA1 missense mutations. In the Parkinson’s disease patients, GCase activity was significantly reduced in monocytes, but not lymphocytes, compared to controls, even when GBA1 mutation carriers were excluded. Monocyte GCase activity correlated with plasma ceramide levels in the Parkinson’s disease patients. Our results add to evidence for GCase dysfunction in idiopathic Parkinson’s disease and warrant further work to determine if monocyte GCase activity associates with Parkinson’s disease progression.
Highlights
Parkinson’s disease (PD) is a common movement disorder, with diagnostic symptoms of resting tremor, bradykinesia and muscle rigidity resulting from degeneration of dopamine producing neurons in the substantia nigra region of the midbrain
GCase activity was defined as the median fluorescence intensity due to PFB-FDglu metabolism in cells without Conduritol B Epoxide (CBE), divided by the median fluorescence intensity of cells treated with CBE
Gaucher’s patients exhibit a higher incidence of PD37, and subsequent genetic analyses of PD patients have demonstrated that GBA1 missense mutations constitute a relatively common risk factor for developing PD4
Summary
Parkinson’s disease (PD) is a common movement disorder, with diagnostic symptoms of resting tremor, bradykinesia and muscle rigidity resulting from degeneration of dopamine producing neurons in the substantia nigra region of the midbrain. The finding that GBA1 mutations increase the risk of developing PD resulted from observation of a higher incidence of PD in patients with the lysosomal storage disorder, Gaucher’s disease, a recessive disorder caused by GBA1 mutations[6]. We have previously shown that GCase activity is reduced in pathologically affected brain tissue from PD subjects without GBA1 mutations[9] This decreased GCase activity was not due to changes in GBA1 mRNA expression, but was associated with impaired lysosomal function and decreased levels of ceramide. These results suggest a broader role for GCase dysfunction in PD beyond just those carriers who have GBA1 mutations. In peripheral immune cells, GCase is most highly expressed in monocytes[29], which comprise only a small fraction of whole blood
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