BRIEF COMMUNICATION
Progressive decline of glucocerebrosidase in aging and Parkinson’s disease Emily M. Rocha1,a, Gaynor A. Smith1,a, Eric Park2, Hongmei Cao2, Eilish Brown2, Penelope Hallett1 & Ole Isacson1 1
Neuroregeneration Laboratories, Harvard Medical School, McLean Hospital, Belmont, Massachusetts, 02478 Shire, 300 Shire Way, Lexington, Massachusetts, 02421
2
Correspondence Ole Isacson, Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA 02478. Tel: (617) 855-3243; Fax: 617-855-3284; E-mail: [email protected] Funding Information This work was supported by the Harvard Stem Cell Institute Translational Neuroscience Fund, the Harold and Ronna Cooper family, the Consolidated Anti-Aging Foundation, the Poul Hansen family, and the Canadian Institute of Health Research.
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.
Received: 19 December 2014; Accepted: 29 December 2014 Annals of Clinical and Translational Neurology 2015; 2(4): 433–438 doi: 10.1002/acn3.177 a These authors contributed equally to this work.
Introduction Parkinson’s disease (PD) is relatively rare before age 40, after age 50 the prevalence rises almost exponentially.1 By the eighth decade, the estimated prevalence in European and North American populations is between 1000 and 3000 cases per 100,000 population.1 This age-related risk may be related to the convergence of genetic impairments and age-related decline in cellular function, which include deficits in degradation pathways and elevated mitochondrial damage. As neurons age, they show signs of increased oxidative stress, disturbances in mitochondrial function, and accumulation of misfolded proteins, which are exacerbated in PD. If the role of lysosomal function could be better defined during the aging process, this
may lead to more effective therapeutic options to treat PD. Neuronal aging is unique because neurons are postmitotic cells, and therefore they rely heavily on protein clearance mechanisms to maintain homeostasis. The two major proteolytic systems responsible for intracellular protein turnover are the autophagy-lysosomal system and the ubiquitin-proteasome system. Aging lysosomal systems undergo dramatic changes including, increased volume and decreased stability and accumulation of indigestible materials.2 This is significant given that lysosomes are responsible for the clearance of proteins, such as asynuclein as well as the removal of damaged organelles, such as mitochondria.3,4 The gene GBA1 encodes for the lysosomal hydrolase glucocerebrosidase (GCase), and
ª 2015 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
433
Progressive Decline of Glucocerebrosidase
E. M. Rocha et al.
Table 1. Parkinson’s disease and control case information. Patient ID
Diagnosis
Age
Sex
PMI
AN15395 AN18990 AN15515 AN17230 AN06318 AN13687 AN06749 AN04648 AN08704 AN06429 AN05049 AN01717 AN01234 AN01219 AN16467 AN06669 AN06400 AN05090 8201 8155 8136 8134 8113 7559 7542 7519 7516 7508 7458 AN01987 AN08649 AN01756 AN01131 AN06530 AN02428 AN18072 AN12683 AN02532 AN12710 AN01459 AN15147 AN02821 AN11926 AN13686 8118 8095 8091 8067 AN05419 AN05440 AN06461 AN18571 AN10634 AN10333
Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s
74 71 73 68 66 73 75 73 70 77 78 79 85 83 79 81 91 87 74 58 76 77 51 78 76 55 63 62 77 74 71 69 68 64 75 73 77 79 87 87 82 81 84 88 83 70 71 75 76 77 87 70 86 74
Male Male Male Male Male Female Male Male Male Male Male Male Male Male Female Male Male Male Male Male Male Female Male Male Male Male Male Male Male Male Male Male Male Male Male Male Male Male Male Male Female Male Male Male Male Male Male Male Male Male Male Male Male Male
18.58 17.41 20.88 26.52 17.83 24.88 23.97 32.68 23.5 23.25 35.17 20.6 20.83 8.86 26.67 23.33 23.48 21.12 24.62 20.47 12.25 20.61 28.82 19 24 24 20 26 29 21.08 12.8 7.1 16.82 17.75 19.42 4.5 20.67 21.12 5.58 12.3 18.08 23 13.82 24.25 15.03 22.92 23.42 26.08 13 18 28 20 20 30
PMI, postmortem interval.
434
disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease
reductions in GCase activity results in the accumulation of the glycolipids glucosylceramide (GluCer) and glucosylsphingosine (GluSph). Heterozygous loss-of-function mutations in GBA1 occur at a frequency of 4–7% in idiopathic PD patients.5–7 Approximately, 6–7% of early onset PD (
Progressive decline of glucocerebrosidase in aging and Parkinson’s disease Emily M. Rocha1,a, Gaynor A. Smith1,a, Eric Park2, Hongmei Cao2, Eilish Brown2, Penelope Hallett1 & Ole Isacson1 1
Neuroregeneration Laboratories, Harvard Medical School, McLean Hospital, Belmont, Massachusetts, 02478 Shire, 300 Shire Way, Lexington, Massachusetts, 02421
2
Correspondence Ole Isacson, Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA 02478. Tel: (617) 855-3243; Fax: 617-855-3284; E-mail: [email protected] Funding Information This work was supported by the Harvard Stem Cell Institute Translational Neuroscience Fund, the Harold and Ronna Cooper family, the Consolidated Anti-Aging Foundation, the Poul Hansen family, and the Canadian Institute of Health Research.
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.
Received: 19 December 2014; Accepted: 29 December 2014 Annals of Clinical and Translational Neurology 2015; 2(4): 433–438 doi: 10.1002/acn3.177 a These authors contributed equally to this work.
Introduction Parkinson’s disease (PD) is relatively rare before age 40, after age 50 the prevalence rises almost exponentially.1 By the eighth decade, the estimated prevalence in European and North American populations is between 1000 and 3000 cases per 100,000 population.1 This age-related risk may be related to the convergence of genetic impairments and age-related decline in cellular function, which include deficits in degradation pathways and elevated mitochondrial damage. As neurons age, they show signs of increased oxidative stress, disturbances in mitochondrial function, and accumulation of misfolded proteins, which are exacerbated in PD. If the role of lysosomal function could be better defined during the aging process, this
may lead to more effective therapeutic options to treat PD. Neuronal aging is unique because neurons are postmitotic cells, and therefore they rely heavily on protein clearance mechanisms to maintain homeostasis. The two major proteolytic systems responsible for intracellular protein turnover are the autophagy-lysosomal system and the ubiquitin-proteasome system. Aging lysosomal systems undergo dramatic changes including, increased volume and decreased stability and accumulation of indigestible materials.2 This is significant given that lysosomes are responsible for the clearance of proteins, such as asynuclein as well as the removal of damaged organelles, such as mitochondria.3,4 The gene GBA1 encodes for the lysosomal hydrolase glucocerebrosidase (GCase), and
ª 2015 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
433
Progressive Decline of Glucocerebrosidase
E. M. Rocha et al.
Table 1. Parkinson’s disease and control case information. Patient ID
Diagnosis
Age
Sex
PMI
AN15395 AN18990 AN15515 AN17230 AN06318 AN13687 AN06749 AN04648 AN08704 AN06429 AN05049 AN01717 AN01234 AN01219 AN16467 AN06669 AN06400 AN05090 8201 8155 8136 8134 8113 7559 7542 7519 7516 7508 7458 AN01987 AN08649 AN01756 AN01131 AN06530 AN02428 AN18072 AN12683 AN02532 AN12710 AN01459 AN15147 AN02821 AN11926 AN13686 8118 8095 8091 8067 AN05419 AN05440 AN06461 AN18571 AN10634 AN10333
Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s Parkinson’s
74 71 73 68 66 73 75 73 70 77 78 79 85 83 79 81 91 87 74 58 76 77 51 78 76 55 63 62 77 74 71 69 68 64 75 73 77 79 87 87 82 81 84 88 83 70 71 75 76 77 87 70 86 74
Male Male Male Male Male Female Male Male Male Male Male Male Male Male Female Male Male Male Male Male Male Female Male Male Male Male Male Male Male Male Male Male Male Male Male Male Male Male Male Male Female Male Male Male Male Male Male Male Male Male Male Male Male Male
18.58 17.41 20.88 26.52 17.83 24.88 23.97 32.68 23.5 23.25 35.17 20.6 20.83 8.86 26.67 23.33 23.48 21.12 24.62 20.47 12.25 20.61 28.82 19 24 24 20 26 29 21.08 12.8 7.1 16.82 17.75 19.42 4.5 20.67 21.12 5.58 12.3 18.08 23 13.82 24.25 15.03 22.92 23.42 26.08 13 18 28 20 20 30
PMI, postmortem interval.
434
disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease
reductions in GCase activity results in the accumulation of the glycolipids glucosylceramide (GluCer) and glucosylsphingosine (GluSph). Heterozygous loss-of-function mutations in GBA1 occur at a frequency of 4–7% in idiopathic PD patients.5–7 Approximately, 6–7% of early onset PD (
