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.
Highlights
The identification of the underlying causes of Parkinson’s disease (PD) is a major challenge, since in most instances, cases present with sporadic disease
The high level of lysosomal enzymes activity observed in substantia nigra, together with the selective reduction of GCase in PD and dementia with Lewy Bodies (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
Summary
The identification of the underlying causes of Parkinson’s disease (PD) is a major challenge, since in most instances, cases present with sporadic disease. The discovery of the genetic determinants of PD would be a major step forward in describing the underlying etiology of the disorder and Chiasserini et al Molecular Neurodegeneration (2015) 10:15 identified in post mortem brain from patients diagnosed with PD either with or without GBA mutations, the decrease being most evident in the substantia nigra, cerebellum and cortex of PD patients [6,7]. This non-selective loss of GCase activity irrespective of mutation status may either represent a global defect in lysosomal enzymes in PD, or may represent the presence of other pathologies such as neuronal loss leading to deficiency. The role of potential confounders (age, sex and post-mortem delay) was determined
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