Hyposmia and cognitive impairment in Gaucher disease patients and carriers

McNeill, Alisdair; Durán, Raquel; Proukakis, Christos; Brás, José; Hughes, D.A.; Mehta, Atuhl; Hardy, John; Wood, Nicholas W.; Schapira, Anthony H.V.

doi:10.1002/mds.24945

Cited by 96 publications

(97 citation statements)

References 27 publications

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“…Olfaction is impaired in GBA mutation carriers and in early PD compared with controls [57,58]. Early olfactory dysfunction is in keeping with the Braak hypothesis that PD pathogenesis commences in peripheral neuronal populations after an as yet unknown insult and that alpha synuclein migrates retrogradely via the enteric, vagal and olfactory tracts to the brainstem, then into cortical and subcortical regions [59].…”

Section: Non Motor Featuressupporting

confidence: 73%

“…Several studies assessed the difference in cognitive performance between PD patients with and without GBA mutations [10,55,58,[61][62][63][65][66][67][68][69][70]; according to a recent meta-analysis, the risk of cognitive impairment is estimated to be 3 times higher for patients with GBA mutations [49]. However, significant differences in cognitive function between PD patients with and without GBA mutations were not confirmed in some studies [13,62,71,72].…”

Section: Non Motor Featuresmentioning

confidence: 99%

“…The baseline data from a longitudinal study found that prodromal signs of PD such and impairment of olfaction, cognition, and motor signs were more frequent in Gaucher Disease (GD) patients and GBA mutation carriers without previous diagnosis of PD than in controls, while no difference was found in REM sleep behavior disorder (RBD) or autonomic dysfunction [58]. A two year follow up of these patients showed that olfactory scores and cognitive performance remained stable but significantly worse than controls; when outcomes for both GD and carriers were considered, RBD, depression and motor signs showed a significant deterioration and, when compared to controls, significant differences in smell, autonomic dysfunction, cognition and motor signs were evident [57].…”

Section: Prodromal Symptoms Of Pd In Patients With Gba Mutationsmentioning

confidence: 99%

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Glucocerebrosidase Mutations in Parkinson Disease

O’Regan

deSouza

Balestrino

et al. 2017

JPD

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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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Section: Non Motor Featuressupporting

confidence: 73%

Section: Non Motor Featuresmentioning

confidence: 99%

Section: Prodromal Symptoms Of Pd In Patients With Gba Mutationsmentioning

confidence: 99%

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Glucocerebrosidase Mutations in Parkinson Disease

O’Regan

deSouza

Balestrino

et al. 2017

JPD

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“…These individuals present with increased frequencies and severities of nonmotor symptoms (e.g., cognitive impairment) that substantially erode their quality of life (16,17). Individuals harboring mutations in GBA1 also have a higher incidence of dementia that is correlated with the presence of neocortical accumulation of aggregates of α-synuclein (18, 19).…”

Section: D409v/d409vmentioning

confidence: 99%

Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies

Sardi¹,

Clarke²,

Viel³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

207

230

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Mutations of GBA1, the gene encoding glucocerebrosidase, represent a common genetic risk factor for developing the synucleinopathies Parkinson disease (PD) and dementia with Lewy bodies. PD patients with or without GBA1 mutations also exhibit lower enzymatic levels of glucocerebrosidase in the central nervous system (CNS), suggesting a possible link between the enzyme and the development of the disease. Previously, we have shown that early treatment with glucocerebrosidase can modulate α-synuclein aggregation in a presymptomatic mouse model of Gaucher-related synucleinopathy (Gba1 D409V/D409V) and ameliorate the associated cognitive deficit. To probe this link further, we have now evaluated the efficacy of augmenting glucocerebrosidase activity in the CNS of symptomatic Gba1 D409V/D409V mice and in a transgenic mouse model overexpressing A53T α-synuclein. Adeno-associated virus-mediated expression of glucocerebrosidase in the CNS of symptomatic Gba1 D409V/D409V mice completely corrected the aberrant accumulation of the toxic lipid glucosylsphingosine and reduced the levels of ubiquitin, tau, and proteinase K-resistant α-synuclein aggregates. Importantly, hippocampal expression of glucocerebrosidase in Gba1 D409V/D409V mice (starting at 4 or 12 mo of age) also reversed their cognitive impairment when examined using a novel object recognition test. Correspondingly, overexpression of glucocerebrosidase in the CNS of A53T α-synuclein mice reduced the levels of soluble α-synuclein, suggesting that increasing the glycosidase activity can modulate α-synuclein processing and may modulate the progression of α-synucleinopathies. Hence, increasing glucocerebrosidase activity in the CNS represents a potential therapeutic strategy for GBA1-related and non-GBA1-associated synucleinopathies, including PD.lysosomal storage diseases | mouse models | MAPT | memory defect M utations in the gene for glucocerebrosidase (GBA1) present the highest genetic risk factor for developing synucleinopathies such as Parkinson disease (PD) and dementia with Lewy bodies (DLB) (1-5). The central nervous system (CNS) of Gaucher patients and carriers who present with parkinsonism and dementia harbor deposits of α-synuclein-positive Lewy bodies (LBs) and Lewy neurites (LNs) in hippocampal neurons and their processes resembling those noted in patients with classical PD and DLB (6, 7). Aspects of these characteristics have also been noted in the CNS of several mouse models of neuropathic and nonneuropathic Gaucher disease (8-10). Consequently, a causal relationship has been suggested between the loss of glucocerebrosidase activity or the lysosomal accumulation of undegraded metabolites and the development of PD and DLB. A more direct link between glucocerebrosidase activity and α-synuclein metabolism has been highlighted by studies of Gaucher cells and mice indicating that a reduction in glucocerebrosidase activity by pharmacological or genetic interventions resulted in increased levels of α-synuclein aggregates (9-12). Moreover, a decrease in glucoce...

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“…More recently, it has been observed that both GD patients and carriers have an increased risk of developing Parkinson disease (PD). Both homozygous and heterozygous GBA1 mutations cause a reduction of glucocerebrosidase (GCase) activity and confer a 20‐ to 30‐fold increased risk for PD 1, 2, 3, 4. It is estimated that approximately 10 to 25% of PD patients have a GBA1 mutation (PD‐ GBA1 ), with the most common mutations being L444P and N370S, and the highest frequency in Ashkenazi patients 1, 2, 3, 4…”

mentioning

confidence: 99%

Ambroxol effects in glucocerebrosidase and α‐synuclein transgenic mice

Migdalska‐Richards

Daly

Bézard

et al. 2016

Annals of Neurology

148

124

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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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Hyposmia and cognitive impairment in Gaucher disease patients and carriers

Cited by 96 publications

References 27 publications

Glucocerebrosidase Mutations in Parkinson Disease

Glucocerebrosidase Mutations in Parkinson Disease

Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies

Ambroxol effects in glucocerebrosidase and α‐synuclein transgenic mice

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