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Progressive decline of glucocerebrosidase in aging and Parkinson's disease.

Rocha EM, Smith GA, Park E, Cao H, Brown E, Hallett P, Isacson O - Ann Clin Transl Neurol (2015)

Bottom Line: 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.These data, demonstrate for the first time that an age-dependent reduction in glucocerebrosidase activity may lower the threshold for developing PD.

View Article: PubMed Central - PubMed

Affiliation: Neuroregeneration Laboratories, Harvard Medical School, McLean Hospital Belmont, Massachusetts, 02478.

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.

No MeSH data available.


Related in: MedlinePlus

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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fig02: 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.

Mentions: GCase activity and levels of GluSph were also assayed in the frontal cortex, hippocampus, and cerebellum of nonGBA1 PD patients and age-matched healthy controls between their 70 and 80 years of age. GCase activity was significantly decreased in the hippocampus (T1,8 = 2.405, P < 0.05) and cerebellum (T1,16 = 2.439, P < 0.05) in nonGBA1 PD patients in comparison to age-matched controls. We found a significant increase in GluSph in the hippocampus (T1,10 = 3.19, P < 0.05) of nonGBA1 PD patients. There was a trend toward an increase for GluSph in the cerebellum of nonGBA1 PD patients in comparison to age-matched controls (Fig.2B).


Progressive decline of glucocerebrosidase in aging and Parkinson's disease.

Rocha EM, Smith GA, Park E, Cao H, Brown E, Hallett P, Isacson O - Ann Clin Transl Neurol (2015)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4402088&req=5

fig02: 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.
Mentions: GCase activity and levels of GluSph were also assayed in the frontal cortex, hippocampus, and cerebellum of nonGBA1 PD patients and age-matched healthy controls between their 70 and 80 years of age. GCase activity was significantly decreased in the hippocampus (T1,8 = 2.405, P < 0.05) and cerebellum (T1,16 = 2.439, P < 0.05) in nonGBA1 PD patients in comparison to age-matched controls. We found a significant increase in GluSph in the hippocampus (T1,10 = 3.19, P < 0.05) of nonGBA1 PD patients. There was a trend toward an increase for GluSph in the cerebellum of nonGBA1 PD patients in comparison to age-matched controls (Fig.2B).

Bottom Line: 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.These data, demonstrate for the first time that an age-dependent reduction in glucocerebrosidase activity may lower the threshold for developing PD.

View Article: PubMed Central - PubMed

Affiliation: Neuroregeneration Laboratories, Harvard Medical School, McLean Hospital Belmont, Massachusetts, 02478.

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.

No MeSH data available.


Related in: MedlinePlus