Glucocerebrosidase gene therapy prevents α-synucleinopathy of midbrain dopamine neurons

Rocha, Emily M.; Smith, Gaynor A.; Park, Eric; Cao, Hongmei; Brown, Eilish; Hayes, Melissa A.; Beagan, Jonathan A.; McLean, Jesse R.; Izen, Sarah C.; Pérez-Torres, Eduardo; Hallett, Peter; Isacson, Ole

doi:10.1016/j.nbd.2015.09.009

Cited by 126 publications

(94 citation statements)

References 41 publications

(64 reference statements)

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“…The use of adeno‐associated viral vectors (AAVs) coding for the GBA1 gene to enhance GCase enzymatic brain activity also holds great promise. It has been reported that the coinjection of AAVs coding for GBA1 and mutated α‐syn in rats prevented dopaminergic neurons from neurodegeneration . Furthermore, the gene therapy field is rapidly changing, with new arrivals being constantly incorporated .…”

Section: Approaches Targeting Gcase For the Treatment Of Synucleinopamentioning

confidence: 99%

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Blandini¹,

Cilia

Cerri³

et al. 2018

Movement Disorders

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Glucocerebrosidase is a lysosomal enzyme. The characterization of a direct link between mutations in the gene coding for glucocerebrosidase (GBA1) with the development of Parkinson's disease and dementia with Lewy bodies has heightened interest in this enzyme. Although the mechanisms through which glucocerebrosidase regulates the homeostasis of α‐synuclein remains poorly understood, the identification of reduced glucocerebrosidase activity in the brains of patients with PD and dementia with Lewy bodies has paved the way for the development of novel therapeutic strategies directed at enhancing glucocerebrosidase activity and reducing α‐synuclein burden, thereby slowing down or even preventing neuronal death. Here we reviewed the current literature relating to the mechanisms underlying the cross talk between glucocerebrosidase and α‐synuclein, the GBA1 mutation‐associated clinical phenotypes, and ongoing therapeutic approaches targeting glucocerebrosidase. © 2018 International Parkinson and Movement Disorder Society

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Section: Approaches Targeting Gcase For the Treatment Of Synucleinopamentioning

confidence: 99%

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Blandini¹,

Cilia

Cerri³

et al. 2018

Movement Disorders

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“…A decrease in glucocerebrosidase activity is thought to induce an increase in CNS α-synuclein/ubiquitin/tau aggregates and to exacerbate behavioral deficits (13,(16)(17)(18)(19)(20)(21)(22). These pathological and behavioral aberrations can be ameliorated by virus-mediated overexpression of exogenous glucocerebrosidase in the CNS, which might act by restoring membrane glycosphingolipids (16,(21)(22)(23).…”

mentioning

confidence: 99%

Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models

Sardi

Viel

Clarke

et al. 2017

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

167

160

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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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“…Numerous recent studies have used recombinant AAV with the genomic elements of AAV serotype 2 packaged with capsid proteins from AAV serotypes 1, 2, 5, 6, 7, 8, or 9 to enhance expression of α‐synuclein in the substantia nigra of wild‐type rats and many other rat models of PD . AAV vectors are typically injected unilaterally in the substantia nigra, which allows the uninjected hemisphere to be used as an internal control for histological analyses and allows locomotor asymmetric behavior to be studied as a measure of nigrostriatal function or degeneration.…”

Section: Viral Vector Animal Models Of Pdmentioning

confidence: 99%

New Developments in Genetic rat models of Parkinson's Disease

Creed

Goldberg

2018

Movement Disorders

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Preclinical research on Parkinson's disease has relied heavily on mouse and rat animal models. Initially, PD animal models were generated primarily by chemical neurotoxins that induce acute loss of dopaminergic neurons in the substantia nigra. On the discovery of genetic mutations causally linked to PD, mice were used more than rats to generate laboratory animals bearing PD-linked mutations because mutagenesis was more difficult in rats. Recent advances in technology for mammalian genome engineering and optimization of viral expression vectors have increased the use of genetic rat models of PD. Emerging research tools include "knockout" rats with disruption of genes in which mutations have been causally linked to PD, including LRRK2, α-synuclein, Parkin, PINK1, and DJ-1. Rats have also been increasingly used for transgenic and viral-mediated overexpression of genes relevant to PD, particularly α-synuclein. It may not be realistic to obtain a single animal model that completely reproduces every feature of a human disease as complex as PD. Nevertheless, compared with mice with the same mutations, many genetic rat animal models of PD better reproduce key aspects of PD including progressive loss of dopaminergic neurons in the substantia nigra, locomotor behavior deficits, and age-dependent formation of abnormal α-synuclein protein aggregates. Here we briefly review new developments in genetic rat models of PD that may have greater potential for identifying underlying mechanisms, for discovering novel therapeutic targets, and for developing greatly needed treatments to slow or halt disease progression. © 2018 International Parkinson and Movement Disorder Society.

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Glucocerebrosidase gene therapy prevents α-synucleinopathy of midbrain dopamine neurons

Cited by 126 publications

References 41 publications

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models

New Developments in Genetic rat models of Parkinson's Disease

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