Glucocerebrosidase in the pathogenesis and treatment of Parkinson disease

Schapira, Anthony H.V.; Gegg, Matthew E.

doi:10.1073/pnas.1300822110

Cited by 57 publications

(51 citation statements)

References 20 publications

(25 reference statements)

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“…These data suggest that GCase deficiency may also play a role in sporadic PD, and, indeed, a loss of GCase activity and protein has been recently reported in the substantia nigra (SN) of some patients with sporadic PD without GBA1 mutation [11]. Overexpressing GCase reduced the accumulation and aggregation of α-synuclein, and improved neuronal function [12,13], validating GCase as a therapeutic target for synucleinopathies [14]. Taken together, these observations suggest that therapeutic interventions that increase GCase stability and activity in the lysosome may represent a new therapeutic approach to break the cycle of α-synuclein accumulation in synucleinopathies such as PD [7,14].…”

Section: Introductionmentioning

confidence: 56%

“…Pharmacological chaperones are orally available small molecules that can access the CNS, bind and stabilize their target protein, and increase GCase activity in the brain without direct administration to the CNS [14,15]. The pharmacological chaperone AT2101 (afegostat-tartrate, isofagomine) specifically and reversibly binds GCase in the ER with high affinity; this stabilizes the active form of the enzyme in the ER and increases trafficking of GCase to lysosomes [16,17].…”

Section: Introductionmentioning

confidence: 99%

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A GCase Chaperone Improves Motor Function in a Mouse Model of Synucleinopathy

et al. 2014

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Mutation of the lysosomal hydrolase acid-β-glucosidase (GCase), which leads to reduced GCase activity, is one of the most frequent genetic risk factors for Parkinson's disease (PD) and promotes α-synuclein accumulation in the brain, a hallmark of PD and other synucleinopathies. Whether targeting GCase pharmacologically is a valid therapeutic strategy for sporadic PD in the absence of GCase mutation is unknown. We have investigated whether increasing the stability, trafficking, and activity of wild-type GCase could be beneficial in synucleinopathies by administering the pharmacological chaperone AT2101 (afegostat-tartrate, isofagomine) to mice that overexpress human wild-type α-synuclein (Thy1-aSyn mice). AT2101 administered orally for 4 months to Thy1-aSyn mice improved motor and nonmotor function, abolished microglial inflammatory response in the substantia nigra, reduced α-synuclein immunoreactivity in nigral dopaminergic neurons, and reduced the number of small α-synuclein aggregates, while increasing the number of large α-synuclein aggregates. These data support the further investigation of pharmacological chaperones that target GCase as a therapeutic approach for sporadic PD and other synucleinopathies, even in the absence of glucocerebrosidase mutations.

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Section: Introductionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

A GCase Chaperone Improves Motor Function in a Mouse Model of Synucleinopathy

et al. 2014

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“…Its chaperone activity appears to be important for targeting GCase for transport to the lysosome. Ambroxol's ability to penetrate the brain–blood barrier, elevate GCase, and reduce α‐synuclein and S129‐phosphorylated α‐synuclein protein levels suggests its potential for development as a treatment for patients with PD and other synucleinopathies 33, 34, 35…”

Section: Discussionmentioning

confidence: 99%

Ambroxol effects in glucocerebrosidase and α‐synuclein transgenic mice

Migdalska‐Richards

Daly

Bézard

et al. 2016

Annals of Neurology

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151

138

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ObjectiveGaucher disease is caused by mutations in the glucocerebrosidase 1 gene that result in deficiency of the lysosomal enzyme glucocerebrosidase. Both homozygous and heterozygous glucocerebrosidase 1 mutations confer an increased risk for developing Parkinson disease. Current estimates indicate that 10 to 25% of Parkinson patients carry glucocerebrosidase 1 mutations. Ambroxol is a small molecule chaperone that has been shown to increase glucocerebrosidase activity in vitro. This study investigated the effect of ambroxol treatment on glucocerebrosidase activity and on α‐synuclein and phosphorylated α‐synuclein protein levels in mice.MethodsMice were treated with ambroxol for 12 days. After the treatment, glucocerebrosidase activity was measured in the mouse brain lysates. The brain lysates were also analyzed for α‐synuclein and phosphorylated α‐synuclein protein levels.ResultsAmbroxol treatment resulted in increased brain glucocerebrosidase activity in (1) wild‐type mice, (2) transgenic mice expressing the heterozygous L444P mutation in the murine glucocerebrosidase 1 gene, and (3) transgenic mice overexpressing human α‐synuclein. Furthermore, in the mice overexpressing human α‐synuclein, ambroxol treatment decreased both α‐synuclein and phosphorylated α‐synuclein protein levels.InterpretationOur work supports the proposition that ambroxol should be further investigated as a potential novel disease‐modifying therapy for treatment of Parkinson disease and neuronopathic Gaucher disease to increase glucocerebrosidase activity and decrease α‐synuclein and phosphorylated α‐synuclein protein levels. Ann Neurol 2016;80:766–775

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“…Interestingly, reduced GCase activity has been found in post mortem samples of PD patients without GBA mutations, suggesting a reduction in activity in PD patients may contribute to PD pathogenesis [17]. As a consequence, targeting of this pathway may provide disease therapy for all PD patients, not just GBA mutation carriers [18].…”

Section: G O'regan Et Al / Gba In Parkinson Diseasementioning

confidence: 99%

Glucocerebrosidase Mutations in Parkinson Disease

O’Regan

deSouza

Balestrino

et al. 2017

JPD

102

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Abstract.Following the discovery of a higher than expected incidence of Parkinson Disease (PD) in Gaucher disease, a lysosomal storage disorder, mutations in the glucocerebrocidase (GBA) gene, which encodes a lysosomal enzyme involved in sphingolipid degradation were explored in the context of idiopathic PD. GBA mutations are now known to be the single largest risk factor for development of idiopathic PD. Clinically, on imaging and pharmacologically, GBA PD is almost identical to idiopathic PD, other than certain features that can be identified in the specialist research setting but not in routine clinical practice. In patients with a known GBA mutation, it is possible to monitor for prodromal signs of PD. The clinical similarity with idiopathic PD and the chance to identify PD at a pre-clinical stage provides a unique opportunity to research therapeutic options for early PD, before major irreversible neurodegeneration occurs. However, to date, the molecular mechanisms which lead to this increased PD risk in GBA mutation carriers are not fully elucidated. Experimental models to define the molecular mechanisms and test therapeutic options include cell culture, transgenic mice and other in vivo models amenable to genetic manipulation, such as drosophilia. Some key pathological pathways of interest in the context of GBA mutations include alpha synuclein aggregation, lysosomal-autophagy axis changes and endoplasmic reticulum stress. Therapeutic agents that exploit these pathways are being developed and include the small molecule chaperone Ambroxol. This review aims to summarise the main features of GBA-PD and provide insights into the pathological relevance of GBA mutations on molecular pathways and the therapeutic implications for PD resulting from investigation of the role of GBA in PD.

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Glucocerebrosidase in the pathogenesis and treatment of Parkinson disease

Cited by 57 publications

References 20 publications

A GCase Chaperone Improves Motor Function in a Mouse Model of Synucleinopathy

A GCase Chaperone Improves Motor Function in a Mouse Model of Synucleinopathy

Ambroxol effects in glucocerebrosidase and α‐synuclein transgenic mice

Glucocerebrosidase Mutations in Parkinson Disease

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