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. 2015 Apr;2(4):433-8.
doi: 10.1002/acn3.177. Epub 2015 Feb 6.

Progressive decline of glucocerebrosidase in aging and Parkinson's disease

Emily M Rocha  1 , Gaynor A Smith  1 , Eric Park  2 , Hongmei Cao  2 , Eilish Brown  2 , Penelope Hallett  1 , Ole Isacson  1
Affiliations

Progressive decline of glucocerebrosidase in aging and Parkinson's disease

Emily M Rocha et al. Ann Clin Transl Neurol. 2015 Apr.

Abstract

The principal risk factor for developing most adult onset neurodegenerative diseases is aging, with incidence rising significantly after age 50. Despite research efforts, the causes of Parkinson's disease (PD) remain unknown. As neurons age, they show signs of diminished lysosomal and mitochondrial function, including increased oxidative stress and accumulation of misfolded proteins, and these changes become exacerbated PD. We show that activity of the lysosomal hydrolase glucocerebrosidase gradually diminishes with age in the substantia nigra and putamen of healthy controls. This reduction is comparable to glucocerebrosidase activity in GBA1-mutation carrier PD patients. These data, demonstrate for the first time that an age-dependent reduction in glucocerebrosidase activity may lower the threshold for developing PD.

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Figures

Figure 1
Figure 1
GCase activity is gradually decreased in the substantia nigra and putamen during normal aging. Brain tissue homogenates from frozen postmortem brain samples were used for measurements of GCase using a 4-methylumbelliferyl activity assay. (A) GCase activity gradually decreased in the substantia nigra and the putamen over the sixth to eighth decade of life in healthy subjects. (B) GCase activity remained consistently low in non-GBA mutation carrying PD patients across the sixth to eighth decade of life in comparison to healthy age-matched controls. (C) By the seventh and eighth decade of life GCase activity levels in healthy subject controls looked similar to PD patients in the substantia nigra and putamen, respectively. GluSph levels were increased in sporadic PD patients at the sixth decade of life in the substantia nigra, but did not change in the putamen. *P < 0.05, two-way ANOVA with Bonferroni post hoc analysis, correlation analysis completed by Pearson test. N = 23/disease cohort. Graphs are expressed as mean ± SEM. GCase, glucocerebrosidase; GluSph, glucosylsphingosine; PD, Parkinson's disease; SEM, standard error of the mean; ANOVA, analysis of variance.
Figure 2
Figure 2
GCase activity is decreased and GluSph is increased in sporadic PD patient brains. GCase is a lysosomal enzyme responsible for the hydrolysis of the lipid substrates GluCer into ceramide and glucose, and GluSph into sphingosine and glucose. Data show that GBA activity is diminished in the putamen, hippocampus, substantia nigra, and cerebellum of sporadic PD patients in comparison to age-matched controls (A). Diminished GBA activity corresponded to accumulation of GluSph in the hippocampus (B). *P < 0.05, unpaired t-test. N = 6–12/group. Graphs are expressed as mean ± SEM. GCase, glucocerebrosidase; GluSph, glucosylsphingosine; GluCer, glucosylceramide; PD, Parkinson's disease; SEM, standard error of the mean; ANOVA, analysis of variance.
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