Glucocerebrosidase deficits in sporadic Parkinson disease

Parkinson disease (PD) is a progressive neurodegenerative movement disorder characterized pathologically by abnormal SNCA/α-synuclein protein inclusions in neurons. Impaired lysosomal autophagic degradation of cellular proteins is implicated in PD pathogenesis and progression. Heterozygous GBA mutations, encoding lysosomal GBA/glucocerebrosidase(glucosidase, beta, acid), are the greatest genetic risk factor for PD, and reduced GBA and SNCA accumulation are related in PD models. Here we review our recent human brain tissue study demonstrating that GBA deficits in sporadic PD are related to the early accumulation of SNCA, and dysregulation of chaperone-mediated autophagy (CMA) pathways and lipidmetabolism

ATP13A2 (PARK9) protein levels are reduced in brain tissue of cases with Lewy bodies

Background: ATP13A2 (PARK9) loss of function mutations are a genetic cause of an early-onset form of Parkinson’s disease (PD), with in vitro studies showing that ATP13A2 deficits lead to lysosomal and mitochondrial dysfunction and α-synuclein accumulation, while elevated ATP13A2 expression reduces α-synuclein toxicity. The three human brain tissue studies assessing changes in ATP13A2 expression in PD produced divergent results; mRNA is increased while protein levels were observed to be either increased or decreased. This apparent conflict in protein levels might have arisen from examining Lewy body disease cases with coexisting Alzheimer-type pathologies.To assess whether ATP13A2 levels in Lewy body disease are modified by Alzheimer-type β-amyloid deposition, we evaluated cases of pure PD and pure dementia with Lewy bodies (DLB) for changes in ATP13A2, α-synuclein and β-amyloid protein levels in cortical regions with and without Lewy bodies.Results: In all Lewy body disease cases, we identified decreased ATP13A2 protein levels that correlated with increases in both α-synuclein and β-amyloid. Partial colocalization was observed between ATP13A2 and α-synuclein in Lewy bodies, whereas ATP13A2 did not colocalize with pathological β-amyloid deposition.Conclusions: Our data show that patients with Lewy body diseases have an overall deficit in ATP13A2 protein levels, with the remaining protein being more insoluble and partially redistributing towards Lewy bodies. This supports the concept that increasing ATP13A2 levels may offer potential therapeutic benefits to patients with Lewy body diseases

Reduced glucocerebrosidase is associated with increased α-synuclein in sporadic Parkinsons disease

Heterozygous mutations in GBA1, the gene encoding lysosomal glucocerebrosidase, are the most frequent known genetic risk factor for Parkinsons disease. Reduced glucocerebrosidase and α-synuclein accumulation are directly related in cell models of Parkinsons disease. We investigated relationships between Parkinsons disease-specific glucocerebrosidase deficits, glucocerebrosidase-related pathways, and α-synuclein levels in brain tissue from subjects with sporadic Parkinsons disease without GBA1 mutations. Brain regions with and without a Parkinsons disease-related increase in α-synuclein levels were assessed in autopsy samples from subjects with sporadic Parkinsons disease (n = 19) and age- and postmortem delay-matched controls (n = 10). Levels of glucocerebrosidase, α-synuclein and related lysosomal and autophagic proteins were assessed by Western blotting. glucocerebrosidase enzyme activity was measured using a fluorimetric assay, and glucocerebrosidase and α-synuclein mRNA expression determined by quantitative PCR. Related sphingolipids were analyzed by mass spectrometry. Multivariate statistical analyses were performed to identify differences between disease groups and regions, with non-parametric correlations used to identify relationships between variables. glucocerebrosidase protein levels and enzyme activity were selectively reduced in the early stages of Parkinsons disease in regions with increased α-synuclein levels although limited inclusion formation, while GBA1 mRNA expression was non-selectively reduced in Parkinsons disease. The selective loss of lysosomal glucocerebrosidase was directly related to reduced lysosomal chaperone-mediated autophagy, increased α-synuclein and decreased ceramide. glucocerebrosidase deficits in sporadic Parkinsons disease are related to the abnormal accumulation of α-synuclein and are associated with substantial alterations in lysosomal chaperone-mediated autophagy pathways and lipid metabolism. Our data suggest that the early selective Parkinsons disease changes are likely due to the redistribution of cellular membrane proteins leading to a chronic reduction in lysosome function in brain regions vulnerable to Parkinsons disease pathology