title: The relationship between glucocerebrosidase mutations and Parkinson disease.
abstract: Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease, whereas Gaucher disease (GD) is the most frequent lysosomal storage disorder caused by homozygous mutations in the glucocerebrosidase (GBA1) gene. Increased risk of developing PD has been observed in both GD patients and carriers. It has been estimated that GBA1 mutations confer a 20- to 30-fold increased risk for the development of PD, and that at least 7-10% of PD patients have a GBA1 mutation. To date, mutations in the GBA1 gene constitute numerically the most important risk factor for PD. The type of PD associated with GBA1 mutations (PD-GBA1) is almost identical to idiopathic PD, except for a slightly younger age of onset and a tendency to more cognitive impairment. Importantly, the pathology of PD-GBA1 is identical to idiopathic PD, with nigral dopamine cell loss, Lewy bodies, and neurites containing alpha-synuclein. The mechanism by which GBA1 mutations increase the risk for PD is still unknown. However, given that clinical manifestation and pathological findings in PD-GBA1 patients are almost identical to those in idiopathic PD individuals, it is likely that, as in idiopathic PD, alpha-synuclein accumulation, mitochondrial dysfunction, autophagic impairment, oxidative and endoplasmic reticulum stress may contribute to the development and progression of PD-GBA1. Here, we review the GBA1 gene, its role in GD, and its link with PD. The impact of glucocerebrosidase 1 (GBA1) mutations on functioning of endoplasmic reticulum (ER), lysosomes, and mitochondria. GBA1 mutations resulting in production of misfolded glucocerebrosidase (GCase) significantly affect the ER functioning. Misfolded GCase trapped in the ER leads to both an increase in the ubiquitin-proteasome system (UPS) and the ER stress. The presence of ER stress triggers the unfolded protein response (UPR) and/or endoplasmic reticulum-associated degradation (ERAD). The prolonged activation of UPR and ERAD subsequently leads to increased apoptosis. The presence of misfolded GCase in the lysosomes together with a reduction in wild-type GCase levels lead to a retardation of alpha-synuclein degradation via chaperone-mediated autophagy (CMA), which subsequently results in alpha-synuclein accumulation and aggregation. Impaired lysosomal functioning also causes a decrease in the clearance of autophagosomes, and so their accumulation. GBA1 mutations perturb normal mitochondria functioning by increasing generation of free radical species (ROS) and decreasing adenosine triphosphate (ATP) production, oxygen consumption, and membrane potential. GBA1 mutations also lead to accumulation of dysfunctional and fragmented mitochondria. This article is part of a special issue on Parkinson disease.
authors: Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK.
authors: Anna
authors: A
authors: Migdalska-Richards
authors: Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK. a.schapira@ucl.ac.uk.
authors: Anthony H V
authors: AH
authors: Schapira
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D005776:Gaucher Disease / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics; D005962:Glucosylceramidase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000201:enzymology / Q000235:genetics; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics*
chemical_list: D005962:Glucosylceramidase
keywords: Gaucher disease; Parkinson disease; alpha-synuclein; glucocerebrosidase 1 (GBA1); lysosome; mitochondria