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

License
getmorefigures.php?uid=PMC4402088&req=5

fig01: 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.

Mentions: Brain tissue from nonGBA1 mutation carrying sporadic PD patients was collected and GCase activity was measured in substantia nigra and putamen. Our data show a clear age-dependent decrease in GCase activity in the substantia nigra that spans the sixth to eighth decade of life (r = −0.643, P < 0.001) in healthy subject controls (Fig.1A). A similar trend was also observed in the putamen across the sixth to eighth decade of life in healthy subject controls. This gradual decline in GCase activity in healthy subject controls became similar to nonGBA1 mutation carrying PD patients by the seventh decade in the substantia nigra (F2,35 = 28.26, P < 0.0001) and the eighth decade in the putamen (F2,32 = 7.16, P < 0.05). GluSph levels were increased in sporadic PD patients at the sixth decade of life (F2,35 = 14.52, P < 0.001) in the substantia nigra. We measured both GluCer and GluSph in sporadic PD patient tissue, however, due to an interfering peak, only GluSph was analyzed.


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

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

fig01: 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.
Mentions: Brain tissue from nonGBA1 mutation carrying sporadic PD patients was collected and GCase activity was measured in substantia nigra and putamen. Our data show a clear age-dependent decrease in GCase activity in the substantia nigra that spans the sixth to eighth decade of life (r = −0.643, P < 0.001) in healthy subject controls (Fig.1A). A similar trend was also observed in the putamen across the sixth to eighth decade of life in healthy subject controls. This gradual decline in GCase activity in healthy subject controls became similar to nonGBA1 mutation carrying PD patients by the seventh decade in the substantia nigra (F2,35 = 28.26, P < 0.0001) and the eighth decade in the putamen (F2,32 = 7.16, P < 0.05). GluSph levels were increased in sporadic PD patients at the sixth decade of life (F2,35 = 14.52, P < 0.001) in the substantia nigra. We measured both GluCer and GluSph in sporadic PD patient tissue, however, due to an interfering peak, only GluSph was analyzed.

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