Objective: To test the correlations between longitudinal measurements of glucocerebrosidase (GCase; encoded by GBA) enzymatic activity and Parkinson’s disease (PD) phenotype in the Parkinson’s Progression Markers Initiative (PPMI) cohort.

Background: Variants in GBA are among the most common genetic risk factors for PD. Carriers of GBA variants may have similar phenotype to sporadic PD, but the rate of motor and cognitive progression is faster among variant carriers. GBA encodes the lysosomal enzyme GCase, which hydrolyzes glucosylceramide and glucosylsphingosine. Reduction in glucocerebrosidase activity has been linked to PD. However, the correlation between glucocerebrosidase activity and PD phenotype was never tested in a longitudinal cohort.

Method: We measured GCase activity in dried blood spots from 1559 samples of participants in the inception PPMI cohort, collected in four annual visits (from baseline visit to Year-3). Participants (PD, n=392; controls, n=175) were fully sequenced for GBA variants by means of genome-wide genotyping arrays, whole-exome sequencing, whole-genome sequencing, Sanger sequencing, and RNA-sequencing.

Results: Fifty-two PD participants (13.4%) and 13 (7.4%) conrols carried a GBA variant. GBA status was strongly associated with GCase activity. Among non-carriers, GCase activity was similar between PD and controls. Among GBA p.E326K carriers (PD, n=20; controls, n=5), activity was significantly lower in PD carriers than control carriers (9.53 µmol/l/h versus 11.68 µmol/l/h, p=0.035). Glucocerebrosidase activity was moderately (r²=0.5) associated with white blood cell (WBC) count. Next, we divided the non-carriers with PD to tertiles based on WBC count-corrected enzymatic activity. Members of the lower tertile had higher MDS-Unified Parkinson’s Disease Rating Scale motor score in the “off” medication examination at year-III exam. Longitudinal analyses demonstrated slight reduction of activity in samples collected earlier on in the study, likely because of longer storage time.

Conclusion: GCase activity is associated with GBA genotype, WBC count, and among p.E326K variant carriers, with PD status. Reduced activity may also be associated with worse phenotype but longer follow up is required to confirm this observation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/longitudinal-measurements-of-glucocerebrosidase-activity-in-parkinsons-patients-and-controls-the-ppmi-study/