β-Glucocerebrosidase activity in GBA -linked Parkinson disease

Abstract

Objective:To test the relationship between clinically relevant types of GBA mutations (none, risk variants, mild mutations, severe mutations) and β-glucocerebrosidase activity in patients with Parkinson's disease (PD) in cross-sectional and longitudinal case-control studies.Methods:481 participants from the Harvard Biomarkers Study (HBS) and the NIH Parkinson Disease Biomarkers Program (PDBP) were analyzed, including 47 PD patients carrying GBA variants (GBA-PD), 247 without a GBA variant (idiopathic PD), and 187 healthy controls. Longitudinal analysis comprised 195 participants with 548 longitudinal measurements over a median follow-up period of 2.0 years (IQR, 1–2 years).Results:β-Glucocerebrosidase activity was low in blood of patients with GBA-PD compared to healthy controls and patients with idiopathic PD, respectively, in HBS (p < 0.001) and PDBP (p < 0.05) in multivariate analyses adjusting for age, sex, blood storage time, and batch. Enzyme activity in patients with idiopathic PD was unchanged. Innovative Enzymatic Quantitative Trait Locus (xQTL) analysis revealed a negative linear association between residual β-glucocerebrosidase activity and mutation type with p < 0.0001. For each increment in the severity of mutation type, a reduction of mean β-glucocerebrosidase activity by 0.85 μmol/l/h (95% CI, -1.17, -0.54) was predicted. In a first longitudinal analysis, increasing mutation severity types were prospectively associated with steeper declines in β-glucocerebrosidase activity during a median two-years of follow-up (p = 0.02).Conclusions:Residual activity of the β-glucocerebrosidase enzyme measured in blood inversely correlates with clinical severity types of GBA mutations in PD. β-Glucocerebrosidase activity is a quantitative endophenotype that can be non-invasively monitored and therapeutically targeted.

Exploring the Genotype–Phenotype Correlation in GBA-Parkinson Disease: Clinical Aspects, Biomarkers, and Potential Modifiers

“…Enzymatic activity of GCase seems to be a promising biomarker in GBA -PD, showing a genotype–phenotype association. Lower GCase enzymatic activity measured in dried blood spots has been reported in GBA -PD patients compared with noncarriers ( 64 ), and after genotypic stratification for GBA variants, increasing severity was associated with decreasing residual GCase activity ( 22 , 62 , 65 ) and longitudinally with a steeper decline of enzymatic activity ( 65 ). When measured in CSF, GCase activity was again significantly reduced in GBA -PD ( 66 ).…”

Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson’s disease enrolled in PPMI

“…GBA encodes the β-glucocerebrosidase enzyme that hydrolyzes the substrate glucosylceramide. In PD patients, increasing severity of the type of GBA mutation is quantitatively associated with decreasing β-glucocerebrosidase activity 4 , increased risk of developing PD 5 , and more rapid cognitive decline 2 , 6 . We and others 6 previously reported that neuropathic Gaucher’s disease (GD) mutations are linked to rapid cognitive decline in PD patients 2 , 6 – 8 .…”

The Mutation Matters: CSF Profiles of GCase, Sphingolipids, α‐Synuclein in PDGBA

“…Heterozygous variants in the GBA gene have been associated with lower GCase activity using a variety of assays in different tissues including blood, CSF, postmortem brain, and induced pluripotent stem cell–derived neurons 25‐29 . Importantly, residual GCase activity in blood was recently reported to be inversely associated with mutation severity, with severe GBA mutations showing the lowest GCase enzyme activity 30 . These findings from the Havard Biomarkers Study and the NINDS Parkinson's Disease Biomarker Program along with the results from TUEPAC‐MIGAP and PPMI robustly confirm that the type of GBA mutation influences GCase enzyme activity in PD.…”