Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains
Matthew E Gegg, Derek Burke, Simon J R Heales, J Mark Cooper, John Hardy, Nicholas W Wood, Anthony H V Schapira, Matthew E Gegg, Derek Burke, Simon J R Heales, J Mark Cooper, John Hardy, Nicholas W Wood, Anthony H V Schapira
Abstract
Objective: Mutations in the glucocerebrosidase gene (GBA) represent a significant risk factor for developing Parkinson disease (PD). We investigated the enzymatic activity of glucocerebrosidase (GCase) in PD brains carrying heterozygote GBA mutations (PD+GBA) and sporadic PD brains.
Methods: GCase activity was measured using a fluorescent assay in cerebellum, frontal cortex, putamen, amygdala, and substantia nigra of PD+GBA (n = 9-14) and sporadic PD brains (n = 12-14). Protein expression of GCase and other lysosomal proteins was determined by western blotting. The relation between GCase, α-synuclein, and mitochondria function was also investigated in vitro.
Results: A significant decrease in GCase activity was observed in all PD+GBA brain areas except the frontal cortex. The greatest deficiency was in the substantia nigra (58% decrease; p < 0.01). GCase activity was also significantly decreased in the substantia nigra (33% decrease; p < 0.05) and cerebellum (24% decrease; p < 0.05) of sporadic PD brains. GCase protein expression was lower in PD+GBA and PD brains, whereas increased C/EBP homologous protein and binding immunoglobulin protein levels indicated that the unfolded protein response was activated. Elevated α-synuclein levels or PTEN-induced putative kinase 1 deficiency in cultured cells had a significant effect on GCase protein levels.
Interpretation: GCase deficiency in PD brains with GBA mutations is a combination of decreased catalytic activity and reduced protein levels. This is most pronounced in the substantia nigra. Biochemical changes involved in PD pathogenesis affect wild-type GCase protein expression in vitro, and these could be contributing factors to the GCase deficiency observed in sporadic PD brains.
Copyright © 2012 American Neurological Association.
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References
- Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher's disease. Lancet. 2008;372:1263–1271.
- Schapira AHV. Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol. 2008;7:97–109.
- Neudorfer O, Giladi N, Elstein D, et al. Occurrence of Parkinson's syndrome in type I Gaucher disease. QJM. 1996;89:691–694.
- Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N Engl J Med. 2004;351:1972–1977.
- Wong K, Sidransky E, Verma A, et al. Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol Genet Metab. 2004;82:192–207.
- Goker-Alpan O, Schiffmann R, LaMarca ME, et al. Parkinsonism among Gaucher disease carriers. J Med Genet. 2004;41:937–940.
- Velayati A, Yu WH, Sidransky E. The role of glucocerebrosidase mutations in Parkinson disease and Lewy body disorders. Curr Neurol Neurosci Rep. 2010;10:190–198.
- Neumann J, Bras J, Deas E, et al. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain. 2009;132:1783–1794.
- Cuervo AM, Wong ESP, Martinez-Vicente M. Protein degradation, aggregation, and misfolding. Mov Disord. 2010;25(suppl 1):S49–S54.
- Alvarez-Erviti L, Rodriguez-Oroz MC, Cooper JM, et al. Chaperone-mediated autophagy markers in Parkinson disease brains. Arch Neurol. 2010;67:1464–1472.
- Dehay B, Bové J, Rodríguez-Muela N, et al. Pathogenic lysosomal depletion in Parkinson's disease. J Neurosci. 2010;30:12535–12544.
- Cuervo AM, Stefanis L, Fredenburg R, et al. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science. 2004;305:1292–1295.
- Gegg ME, Schapira AHV. PINK1-parkin-dependent mitophagy involves ubiquitination of mitofusins 1 and 2: implications for Parkinson disease pathogenesis. Autophagy. 2011;7:243–245.
- Sardi SP, Clarke J, Kinnecom C, et al. CNS expression of glucocerebrosidase corrects alpha-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy. Proc Natl Acad Sci U S A. 2011;108:12101–12106.
- Xu YH, Sun Y, Ran H, et al. Accumulation and distribution of α-synuclein and ubiquitin in the CNS of Gaucher disease mouse models. Mol Genet Metab. 2011;102:436–447.
- Manning-Boǧ AB, Schüle B, Langston JW. Alpha-synuclein-glucocerebrosidase interactions in pharmacological Gaucher models: a biological link between Gaucher disease and parkinsonism. Neurotoxicology. 2009;30:1127–1132.
- Cullen V, Sardi SP, Ng J, et al. Acid β-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter α-synuclein processing. Ann Neurol. 2011;69:940–953.
- Mazzulli JR, Xu Y-H, Sun Y, et al. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011;146:37–52.
- Yap TL, Gruschus JM, Velayati A, et al. Alpha-synuclein interacts with glucocerebrosidase providing a molecular link between Parkinson and Gaucher diseases. J Biol Chem. 2011;286:28080–28088.
- Wenger DA, Clark C, Sattler M, Wharton C. Synthetic substrate beta-glucosidase activity in leukocytes: a reproducible method for the identification of patients and carriers of Gaucher's disease. Clin Genet. 1978;13:145–153.
- Boot RG, Verhoek M, Donker-Koopman W, et al. Identification of the non-lysosomal glucosylceramidase as beta-glucosidase 2. J Biol Chem. 2007;282:1305–1312.
- Wendeler M, Sandhoff K. Hexosaminidase assays. Glycoconj J. 2009;26:945–952.
- Klionsky DJ, Abeliovich H, Agostinis P, et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy. 2008;4:151–175.
- Ron I, Horowitz M. ER retention and degradation as the molecular basis underlying Gaucher disease heterogeneity. Hum Mol Genet. 2005;14:2387–2398.
- Mu T-W, Ong DST, Wang Y-J, et al. Chemical and biological approaches synergize to ameliorate protein-folding diseases. Cell. 2008;134:769–781.
- Doyle KM, Kennedy D, Gorman AM, et al. Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders. J Cell Mol Med. 2011;15:2025–2039.
- Witte MD, Kallemeijn WW, Aten J, et al. Ultrasensitive in situ visualization of active glucocerebrosidase molecules. Nat Chem Biol. 2010;6:907–913.
- Gegg ME, Cooper JM, Schapira AHV, Taanman J-W. Silencing of PINK1 expression affects mitochondrial DNA and oxidative phosphorylation in dopaminergic cells. PLoS ONE. 2009;4:e4756.
- Wood-Kaczmar A, Gandhi S, Yao Z, et al. PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons. PLoS ONE. 2008;3:e2455.
- Reczek D, Schwake M, Schröder J, et al. LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase. Cell. 2007;131:770–783.
- Choi JH, Stubblefield B, Cookson MR, et al. Aggregation of α-synuclein in brain samples from subjects with glucocerebrosidase mutations. Mol Genet Metab. 2011;104:185–188.
- Cooper AA, Gitler AD, Cashikar A, et al. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science. 2006;313:324–328.
- Thayanidhi N, Helm JR, Nycz DC, et al. Alpha-synuclein delays endoplasmic reticulum (ER)-to-Golgi transport in mammalian cells by antagonizing ER/Golgi SNAREs. Mol Biol Cell. 2010;21:1850–1863.
- Lu J, Chiang J, Iyer RR, et al. Decreased glucocerebrosidase activity in Gaucher disease parallels quantitative enzyme loss due to abnormal interaction with TCP1 and c-Cbl. Proc Natl Acad Sci U S A. 2010;107:21665–21670.
- Farfel-Becker T, Vitner E, Dekel H, et al. No evidence for activation of the unfolded protein response in neuronopathic models of Gaucher disease. Hum Mol Genet. 2009;18:1482–1488.
- Bouman L, Schlierf A, Lutz AK, et al. Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress. Cell Death Differ. 2011;18:769–782.
- Westerlund M, Belin AC, Anvret A, et al. Cerebellar alpha-synuclein levels are decreased in Parkinson's disease and do not correlate with SNCA polymorphisms associated with disease in a Swedish material. FASEB J. 2008;22:3509–3514.
- Mann VM, Cooper JM, Krige D, et al. Brain, skeletal muscle and platelet homogenate mitochondrial function in Parkinson's disease. Brain. 1992;115:333–342.
Source: PubMed