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 .
Highlights
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
Genotyping for L444P, N370S, and R120W mutations Sequencing of glucocerebrosidase 1 (GBA1) exons (30 cases) Genotyping for L444P, D409H, R120W, L174P, and Q497R mutations Genotyping for N370S mutation Genotyping for L444P mutation Genotyping for L444P, N370S, F213I, and R353W mutations Genotyping for L444P and N370S mutations Genotyping for L444P, RecNciI, and R120W mutations Sequencing of GBA1 exons c.334_338delCAGAA L264I, L314V, R163Q, F213I, E326K, S364S, F347L, V375L, L444P, RecNciI, and Q497R L444P, N386K, P428S, IVS2þ1G>A, IVS9þ3G>C, IVS10-9_10GT>AG, and c.1309delG L444P
Administration of a molecular chaperone AT2101 led to GCase increase in the brain and resulted in improvement of both motor function and neuropathological manifestations in Thy1-aSyn mice (Richter et al 2014). These results show that an increase in GCase activity achieved by administration of molecular chaperones might significantly improve clinical and biochemical manifestations of synucleinopathies, even those without GBA1 mutations, and so further development of small molecular chaperones gives a great promise for finding a successful treatment for PD associated with GBA1 mutations (PD-GBA1), and for idiopathic PD and other synucleinopathies
Summary
Gaucher disease (GD) is named after Dr Philippe Gaucher who, in 1882, first described a young woman with an enlarged spleen containing unusual looking cells (Gaucher 1882). The ability of small molecular chaperones to bind to misfolded GCase (and subsequently to induce proper folding of mutant GCase that in turn would increase functional GCase levels in the lysosomes) is important, as it has been shown that majority of GBA1 mutations lead to the production of misfolded GCase (Sawkar et al 2002; Bernier et al 2004; Suzuki et al 2009; Patnaik et al 2012). Available data from ambroxol-treated wild-type and transgenic mice carrying human GBA1 mutations has convincingly shown increase in GCase activity in the peripheral organs, but variable change in the brain. Retrospective genetic analysis identified GBA1 mutations in 17% of those who had undergone deepbrain stimulation, and in whom clinical effect was as good as those without mutations (Angeli et al 2013)
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