1. Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains
- Author
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Nicholas W. Wood, J. Mark Cooper, Derek Burke, Anthony H.V. Schapira, Simon J.R. Heales, Matthew E. Gegg, and John Hardy
- Subjects
Male ,Heterozygote ,medicine.medical_specialty ,Pathology ,Substantia nigra ,Biology ,medicine.disease_cause ,Gene Expression Regulation, Enzymologic ,Neuroblastoma ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Chaperone-mediated autophagy ,Cell Line, Tumor ,Internal medicine ,medicine ,Humans ,Immunoprecipitation ,RNA, Small Interfering ,Aged ,030304 developmental biology ,Aged, 80 and over ,Alpha-synuclein ,0303 health sciences ,Mutation ,Gaucher Disease ,Parkinsonism ,Parkinson Disease ,Heterozygote advantage ,Original Articles ,Middle Aged ,medicine.disease ,Sphingolipid ,Mitochondria ,3. Good health ,Substantia Nigra ,Endocrinology ,nervous system ,Neurology ,chemistry ,alpha-Synuclein ,Glucosylceramidase ,Female ,Neurology (clinical) ,Protein Kinases ,Glucocerebrosidase ,030217 neurology & neurosurgery - Abstract
The lysosomal storage disorder Gaucher disease (GD) is caused by autosomal recessive mutations in the glucocerebrosidase (GBA) gene. GBA encodes a lysosomal enzyme (GCase) that catalyses the metabolism of the sphingolipid glucosylceramide to ceramide and glucose. Deficiency of GCase activity results in accumulation of substrate in the lysosomes of several tissues, including brain. Mutations in GBA result in 3 clinical manifestations. Type 1 GD occurs in both children and adults and predominantly impacts on the non-neuronal organs, whereas types 2 and 3 have an onset in childhood and adolescence, respectively, and exhibit neurological deficits.1 Parkinson disease (PD) is primarily characterized by the motor symptoms of resting tremor, bradykinesia, rigidity, and postural instability. Pathological hallmarks include loss of dopaminergic neurons from the substantia nigra (SN) and the presence of cytoplasmic inclusions known as Lewy bodies in the surviving cells of affected brain regions.2 Typical parkinsonism is among the neurological complications of GD (including type 1).3, 4 The neuropathology of GD brains includes the typical hallmarks of PD, such as cortical and brainstem Lewy bodies.5 Heterozygote carriers of GBA mutations also have an increased frequency of PD, and these mutations are the most common genetic risk factor for developing the disease.6–8 Although the pathogenesis of PD is still unknown, the accumulation of α-synuclein and other ubiquitinated proteins in Lewy bodies has implicated protein mishandling as a putative cause. The proteasome and lysosomes are the 2 principal mechanisms for degrading cellular constituents. Autophagy utilizes lysosomes to degrade long-lived proteins, misfolded/aggregated proteins, and organelles such as mitochondria.9 Defective autophagy and/or lysosomal depletion have been implicated in PD.10–13 Cellular or animal models of GCase deficiency have caused α-synuclein accumulation.14–18 GCase has also been suggested to bind directly with α-synuclein in lysosomes19 and the GCase substrate glucosylceramide stabilizes soluble oligomeric α-synuclein species.18 These observations have led to the notion that GCase deficiency might contribute to the α-synuclein aggregation characteristic of PD pathology. Despite the recognized association between GBA mutations and PD, it is unknown how heterozygous GBA mutations affect GCase activity in PD brains. In this paper, we provide the first report of the activity of GCase in several regions of PD brains from GBA mutation carriers and sporadic PD brains. GCase deficiency was greatest in the SN of PD brains with GBA mutations. This loss of activity was in part mediated by a decrease in GCase protein levels. GCase activity was also significantly decreased in the SN of sporadic PD brains.
- Published
- 2012