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Glucocerebrosidase and Parkinson disease: Recent advances.
Mol Cell Neurosci 2015; 66(Pt A):37-42MC

Abstract

Mutations of the glucocerebrosidase (GBA) gene are the most important risk factor yet discovered for Parkinson disease (PD). Homozygous GBA mutations result in Gaucher disease (GD), a lysosomal storage disorder. Heterozygous mutations have not until recently been thought to be associated with any pathological process. However, it is clear that the presence of a GBA mutation in homozygous or heterozygous form is associated with an approximately 20-fold increase in the risk for PD, with little if any difference in risk burden related to gene dose. Most studies suggest that 5-10% of PD patients have GBA mutations, although this figure is greater in the Ashkenazi population and may be an underestimate overall if the entire exome is not sequenced. GBA-associated PD is clinically indistinguishable from idiopathic PD, except for slightly earlier age of onset and a greater frequency of cognitive impairment. Pathological and imaging features, and response to pharmacotherapy are identical to idiopathic PD. GBA mutations result in reduced enzyme activity and mutant protein may become trapped in the endoplasmic reticulum (ER) leading to unfolded protein response and ER associated degradation and stress. Both mechanisms may be relevant in GD and PD pathogenesis and lead to impaired lysosomal function. Of particular relevance to PD is the interaction of glucocerebrosidase enzyme (GCase) with alpha-synuclein (SNCA). There appears to be a bi-directional reciprocal relationship between GCase levels and those of SNCA. Thus reduced GCase in GBA mutation PD brain is associated with increased SNCA, and increased SNCA deposition is associated with reduced GCase even in GBA wild-type PD brains. It is noteworthy that GBA mutations are also associated with an increase in risk for dementia with Lewy bodies, another synucleinopathy. It has been suggested that the relationship between GCase and SNCA may be leveraged to reduce SNCA levels in PD by enhancing GCase levels and activity. This hypothesis has been confirmed in GBA mutant mice, PD patient fibroblasts and cells with SNCA overexpression, and offers an important target pathway for future neuroprotection therapy in PD. This article is part of a Special Issue entitled 'Neuronal Protein'.

Authors+Show Affiliations

Department of Clinical Neurosciences, UCL Institute of Neurology, UCL Royal Free Campus, Rowland Hill Street, London NW3 2PF, United Kingdom. Electronic address: a.schapira@ucl.ac.uk.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

25802027

Citation

Schapira, Anthony H V.. "Glucocerebrosidase and Parkinson Disease: Recent Advances." Molecular and Cellular Neurosciences, vol. 66, no. Pt A, 2015, pp. 37-42.
Schapira AH. Glucocerebrosidase and Parkinson disease: Recent advances. Mol Cell Neurosci. 2015;66(Pt A):37-42.
Schapira, A. H. (2015). Glucocerebrosidase and Parkinson disease: Recent advances. Molecular and Cellular Neurosciences, 66(Pt A), pp. 37-42. doi:10.1016/j.mcn.2015.03.013.
Schapira AH. Glucocerebrosidase and Parkinson Disease: Recent Advances. Mol Cell Neurosci. 2015;66(Pt A):37-42. PubMed PMID: 25802027.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glucocerebrosidase and Parkinson disease: Recent advances. A1 - Schapira,Anthony H V, Y1 - 2015/03/20/ PY - 2015/02/03/received PY - 2015/03/10/revised PY - 2015/03/12/accepted PY - 2015/3/25/entrez PY - 2015/3/25/pubmed PY - 2016/2/18/medline KW - Alpha-synuclein KW - Glucocerebrosidase KW - Lysosome KW - Neuroprotection KW - Parkinson disease SP - 37 EP - 42 JF - Molecular and cellular neurosciences JO - Mol. Cell. Neurosci. VL - 66 IS - Pt A N2 - Mutations of the glucocerebrosidase (GBA) gene are the most important risk factor yet discovered for Parkinson disease (PD). Homozygous GBA mutations result in Gaucher disease (GD), a lysosomal storage disorder. Heterozygous mutations have not until recently been thought to be associated with any pathological process. However, it is clear that the presence of a GBA mutation in homozygous or heterozygous form is associated with an approximately 20-fold increase in the risk for PD, with little if any difference in risk burden related to gene dose. Most studies suggest that 5-10% of PD patients have GBA mutations, although this figure is greater in the Ashkenazi population and may be an underestimate overall if the entire exome is not sequenced. GBA-associated PD is clinically indistinguishable from idiopathic PD, except for slightly earlier age of onset and a greater frequency of cognitive impairment. Pathological and imaging features, and response to pharmacotherapy are identical to idiopathic PD. GBA mutations result in reduced enzyme activity and mutant protein may become trapped in the endoplasmic reticulum (ER) leading to unfolded protein response and ER associated degradation and stress. Both mechanisms may be relevant in GD and PD pathogenesis and lead to impaired lysosomal function. Of particular relevance to PD is the interaction of glucocerebrosidase enzyme (GCase) with alpha-synuclein (SNCA). There appears to be a bi-directional reciprocal relationship between GCase levels and those of SNCA. Thus reduced GCase in GBA mutation PD brain is associated with increased SNCA, and increased SNCA deposition is associated with reduced GCase even in GBA wild-type PD brains. It is noteworthy that GBA mutations are also associated with an increase in risk for dementia with Lewy bodies, another synucleinopathy. It has been suggested that the relationship between GCase and SNCA may be leveraged to reduce SNCA levels in PD by enhancing GCase levels and activity. This hypothesis has been confirmed in GBA mutant mice, PD patient fibroblasts and cells with SNCA overexpression, and offers an important target pathway for future neuroprotection therapy in PD. This article is part of a Special Issue entitled 'Neuronal Protein'. SN - 1095-9327 UR - https://www.unboundmedicine.com/medline/citation/25802027/Glucocerebrosidase_and_Parkinson_disease:_Recent_advances_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1044-7431(15)00042-1 DB - PRIME DP - Unbound Medicine ER -