Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

Beavan, Michelle; Schapira, Anthony H.V.

doi:10.3109/07853890.2013.849003

Cited by 99 publications

(97 citation statements)

References 221 publications

(293 reference statements)

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“…Recent clinical studies indicate that GBA status may also impact the natural history of PD. Patients who harbor GBA mutations present a higher prevalence and severity of bradykinesia, motor complications, and cognitive decline (3)(4)(5).…”

mentioning

confidence: 99%

Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models

Sardi

Viel

Clarke

et al. 2017

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

178

161

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Mutations in the glucocerebrosidase gene (GBA) confer a heightened risk of developing Parkinson's disease (PD) and other synucleinopathies, resulting in a lower age of onset and exacerbating disease progression. However, the precise mechanisms by which mutations in GBA increase PD risk and accelerate its progression remain unclear. Here, we investigated the merits of glucosylceramide synthase (GCS) inhibition as a potential treatment for synucleinopathies. Two murine models of synucleinopathy (a Gaucher-related synucleinopathy model, Gba D409V/D409V and a A53T-α-synuclein overexpressing model harboring wild-type alleles of GBA, A53T-SNCA mouse model) were exposed to a brain-penetrant GCS inhibitor, GZ667161. Treatment of Gba D409V/D409V mice with the GCS inhibitor reduced levels of glucosylceramide and glucosylsphingosine in the central nervous system (CNS), demonstrating target engagement. Remarkably, treatment with GZ667161 slowed the accumulation of hippocampal aggregates of α-synuclein, ubiquitin, and tau, and improved the associated memory deficits. Similarly, prolonged treatment of A53T-SNCA mice with GZ667161 reduced membrane-associated α-synuclein in the CNS and ameliorated cognitive deficits. The data support the contention that prolonged antagonism of GCS in the CNS can affect α-synuclein processing and improve behavioral outcomes. Hence, inhibition of GCS represents a diseasemodifying therapeutic strategy for GBA-related synucleinopathies and conceivably for certain forms of sporadic disease.Parkinson's disease | GBA mutations | glucosylceramide synthase | Gaucher disease | Lewy body dementia

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mentioning

confidence: 99%

Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models

Sardi

Viel

Clarke

et al. 2017

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

178

161

View full text Add to dashboard Cite

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“…Whether the accumulated glucosylsphingosine orchestrates this pathway remains to be determined. In addition, of interest is the fact that GBA1 mutations represent the most important risk factor for developing α-synucleopathies such as Parkinson disease [144]. It is still a matter of debate whether alterations in GlcCer (or Cer) metabolism primarily contribute or initiate the accumulation and aggregation of α-synuclein and other proteins including the amyloid precursor protein [145].…”

Section: Defects Of Glucosylceramide Metabolismmentioning

confidence: 99%

Monogenic neurological disorders of sphingolipid metabolism

Sabourdy

Astudillo

Colacios

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…This gene is responsible for approximately 5-10% of GBA mutations in PD patients. 9 GBA mutation is now regarded as the most important genetic predisposing risk factor for PD and enhancing GCase activity or alteration of activity of chaperone proteins, such as HSP90 (heat shock protein 90), may be beneficial. 9 In this instance, personalised medicine will consist of a dual precision strategy of combining chaperone and GCase augmentation-based 'cocktail' therapy.…”

Section: Personalised Medicinementioning

confidence: 99%

“…9 GBA mutation is now regarded as the most important genetic predisposing risk factor for PD and enhancing GCase activity or alteration of activity of chaperone proteins, such as HSP90 (heat shock protein 90), may be beneficial. 9 In this instance, personalised medicine will consist of a dual precision strategy of combining chaperone and GCase augmentation-based 'cocktail' therapy. Pharmacogenetics, on the other hand, will address inherited genetic differences in drug metabolic pathways which can influence individual clinical responses to drugs as well as adverse events.…”

Section: Personalised Medicinementioning

confidence: 99%

The Future of Parkinson’s Treatment – Personalised and Precision Medicine

Titova

Jenner

2017

European Neurological Review

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T he modern concept of Parkinson's disease (PD) has changed and evolved and we consider Parkinson's to be a multi-neurotransmitter dysfunction-related disorder with central and peripheral nervous system involvement. The clinical expression is thus a mixture of the outwardly evident motor symptoms and a range of 'hidden' non-motor symptoms. The complex underlying neuropathology of PD calls for a reassessment of the treatment strategies currently used. Treatment of PD is guideline-driven and in most cases based on a dopamine replacement strategy or surgical manipulation of brain dopaminergic pathways. Treatment of many non-dopaminergic non-motor and some motor symptoms, which have major effects on quality of life, continue to remain a key unmet need. Like in other chronic conditions such as rheumatology, the role of personalised medicine in PD needs to be increasingly considered. Personalised medicine for PD is not just a genetic approach to treatment but encompasses various strands of treatment. These include pharmacogenetic, pharmacological, as well as socio-demographic and lifestyle-related issues. Once these 'enablers' of personalised medicine are considered then satisfactory treatment for our patients with Parkinson's can be achieved in an individualised manner. Future therapy for PD should move in that direction. KeywordsParkinson's disease, non-motor symptoms, quality of life, personalised medicine, precision medicine Disclosure: Nataliya Titova, Peter Jenner and K Ray Chaudhuri have nothing to declare in relation to this article. This article is a short opinion piece and has not been submitted to external peer reviewers. No funding was received for the publication of this article.Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. 1 Many motor symptoms of PD can be partially reversed by DRT as well as more invasive therapies such as deep brain stimulation (DBS) of the subthalamic nucleus. However, many challenges remain both in the short and long term. Largely, these relate to the fact that the modern definition of PD has changed and the condition is now regarded as a complex disease with syndromic presentations manifesting as non-motor subtypes.2,3 Non-dopaminergic presentations, such as cholinergic, serotonergic and noradrenergic, can dominate the clinical phenotype of PD and form the basis of the recently described non-motor subtypes of PD. [3][4][5] This heterogeneity of neuropathology and diversity of presentation needs treatment tailored to suit the clinical phenotypes. However, globally PD still continues to be treated by guideline-based alg...

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Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

Cited by 99 publications

References 221 publications

Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models

Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models

Monogenic neurological disorders of sphingolipid metabolism

The Future of Parkinson’s Treatment – Personalised and Precision Medicine

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