Selective loss of glucocerebrosidase activity in sporadic Parkinson’s disease and dementia with Lewy bodies

Abstract

BackgroundLysosomal dysfunction is thought to be a prominent feature in the pathogenetic events leading to Parkinson’s disease (PD). This view is supported by the evidence that mutations in GBA gene, coding the lysosomal hydrolase β-glucocerebrosidase (GCase), are a common genetic risk factor for PD. Recently, GCase activity has been shown to be decreased in substantia nigra and in cerebrospinal fluid of patients diagnosed with PD or dementia with Lewy Bodies (DLB). Here we measured the activity of GCase and other endo-lysosomal enzymes in different brain regions (frontal cortex, caudate, hippocampus, substantia nigra, cerebellum) from PD (n = 26), DLB (n = 16) and age-matched control (n = 13) subjects, screened for GBA mutations. The relative changes in GCase gene expression in substantia nigra were also quantified by real-time PCR. The role of potential confounders (age, sex and post-mortem delay) was also determined.FindingsSubstantia nigra showed a high activity level for almost all the lysosomal enzymes assessed. GCase activity was significantly decreased in the caudate (−23%) and substantia nigra (−12%) of the PD group; the same trend was observed in DLB. In both groups, a decrease in GCase mRNA was documented in substantia nigra. No other lysosomal hydrolase defects were determined.ConclusionThe high level of lysosomal enzymes activity observed in substantia nigra, together with the selective reduction of GCase in PD and DLB patients, further support the link between lysosomal dysfunction and PD pathogenesis, favoring the possible role of GCase as biomarker of synucleinopathy. Mapping the lysosomal enzyme activities across different brain areas can further contribute to the understanding of the role of lysosomal derangement in PD and other synucleinopathies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0010-2) contains supplementary material, which is available to authorized users.

Impact of glucocerebrosidase mutations on motor and nonmotor complications in Parkinson's disease

“…The pathogenic loop may facilitate neurodegeneration in GD-associated PD brain, resulting in early development of dementia or psychosis as shown in the present study. Several recent researches propose the possibility that the similar mechanism as in PD with GBA mutations exists even in idiopathic PD brain (Alcalay et al, 2015;Chiasserini et al, 2015;Gegg et al, 2012;Murphy et al, 2014). On the other hand, the impacts of GD-associated GBA mutations for the development of motor complications such as wearing-off and dyskinesia were not statistically significant, suggesting other pathophysiological mechanisms in the striatal circuit brought out after long-term therapy especially by L-dopa.…”

LRRK2 deficiency impacts ceramide metabolism in brain

“…On the other hand, in idiopathic PD patients as well as in PD patients carrying GBA1 mutations and in GD patients, a decrease in GBA1 level is usually associated with a decrease in GBA1 activity [27,33,[35][36][37][38][39][40] (Table 1). The overall picture that emerges from this analysis is that Cer metabolism is important in PD etiopathogenesis.…”

Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

“…Moreover, stronger GBA1 loss‐of‐function alleles have also been implicated with more severe motor phenotypes and increased risk of nonmotor manifestations, including hyposmia, cognitive impairment, and dementia . Interestingly, reduced GCase enzymatic activity has also been documented in sporadic PD (without known GBA1 mutations) . Lastly, individuals with GD are also at risk of developing PD.…”