Abstract
Mutations in the GBA gene, encoding the lysosomal hydrolase glucocerebrosidase (GCase), are the most common known genetic risk factor for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). The present study aims to gain more insight into changes in lysosomal activity in different brain regions of sporadic PD and DLB patients, screened for GBA variants. Enzymatic activities of GCase, β-hexosaminidase, and cathepsin D were measured in the frontal cortex, putamen, and substantia nigra (SN) of a cohort of patients with advanced PD and DLB as well as age-matched non-demented controls (n = 15/group) using fluorometric assays. Decreased activity of GCase (− 21%) and of cathepsin D (− 15%) was found in the SN and frontal cortex of patients with PD and DLB compared to controls, respectively. Population stratification was applied based on GBA genotype, showing substantially lower GCase activity (~ − 40%) in GBA variant carriers in all regions. GCase activity was further significantly decreased in the SN of PD and DLB patients without GBA variants in comparison to controls without GBA variants. Our results show decreased GCase activity in brains of PD and DLB patients with and without GBA variants, most pronounced in the SN. The results of our study confirm findings from previous studies, suggesting a role for GCase in GBA-associated as well as sporadic PD and DLB.
Highlights
Converging evidence from genetic, pathological, and experimental studies has suggested that impairment of the autophagy-lysosomal pathway (ALP) is a key pathological event in the pathogenesis of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) [1, 2]
GCase activity was significantly decreased in the substantia nigra (SN) of PD and DLB patients compared to controls (− 21%; p = 0.02), while this effect was not significant in other studied brain regions (Fig. 2b, d)
GCase activity was significantly decreased in the SN of PD patients compared to controls, while lower cathepsin D (CathD) activity was found in the frontal cortex of DLB patients compared to controls *p < 0.05 trend in DLB patients (− 20%; p = 0.06)
Summary
Converging evidence from genetic, pathological, and experimental studies has suggested that impairment of the autophagy-lysosomal pathway (ALP) is a key pathological event in the pathogenesis of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) [1, 2]. Mutations in numerous genes encoding for ALP components have been associated with increased risk to develop PD, including Glucosidase Beta Acid 1 (GBA) [3]. Homozygous GBA mutations cause Gaucher disease (GD), and heterozygous GBA mutations form the major genetic risk factor for PD and DLB. The prevalence of GBA variants is estimated 5–10% in PD and DLB patients and higher in certain studied populations, among Ashkenazi Jews (~ 20%) [4,5,6]. Recent studies showed GBA mutations impact the clinical phenotype of PD and DLB, as their presence has been associated with
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