Glucocerebrosidase deficiency in dopaminergic neurons induces microglial activation without neurodegeneration

Soria, F.; Engeln, Michel; Martínez-Vicente, Marta; Glangetas, Christelle; López-González, María José; Doveró, Sandra; Dehay, Benjamin; Normand, Elisabeth; Vila, Miquel; Favereaux, Alexandre; Georges, François; Bianco, Christophe Lo; Bézard, Erwan; Fernagut, Pierre Olivier

doi:10.1093/hmg/ddx120

Cited by 36 publications

(27 citation statements)

References 53 publications

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“…Since gba haploinsufficency did not result in significantly enhanced SNCA levels or abundance of SNCA pathology in terminal mice, another, yet unknown secondary function of GCase protein in distinct neuronal populations may initiate or contribute to the earlier and more severe symptoms in gba +/− // SNCA A53T mice. This is supported by a study of dopaminergic neurons from aged mice with a conditional GBA1 knock-out, which had no motor dysfunction and no midbrain accumulation of endogenous SNCA [40]. It has been proposed that deficient GCase promotes cellular cascades contributing to earlier Parkinson pathogenesis and synaptic dysfunction [16].…”

Section: Discussionmentioning

confidence: 97%

Glucocerebrosidase haploinsufficiency in A53T α-synuclein mice impacts disease onset and course

Tayebi

Parisiadou

Berhe

et al. 2017

Molecular Genetics and Metabolism

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Mutations in GBA1 encountered in Gaucher disease are a leading risk factor for Parkinson disease and associated Lewy body disorders. Many GBA1 mutation carriers, especially those with severe or null GBA1 alleles, have earlier and more progressive parkinsonism. To model the effect of partial glucocerebrosidase deficiency on neurological progression in vivo, mice with a human A53T α-synuclein (SNCAA53T) transgene were crossed with heterozygous null gba mice (gba+/−). Survival analysis of 84 mice showed that in gba+/−//SNCAA53T hemizygotes and homozygotes, the symptom onset was significantly earlier than in gba+/+//SNCAA53T mice (p-values 0.023–0.0030), with exacerbated disease progression (p-value < 0.0001). Over-expression of SNCAA53T had no effect on glucocerebrosidase levels or activity. Immunoblotting demonstrated that gba haploinsufficiency did not lead to increased levels of either monomeric SNCA or insoluble high molecular weight SNCA in this model. Immunohistochemical analyses demonstrated that the abundance and distribution of SNCA pathology was also unaltered by gba haploinsufficiency. Thus, while the underlying mechanism is not clear, this model shows that gba deficiency impacts the age of onset and disease duration in aged SNCAA53T mice, providing a valuable resource to identify modifiers, pathways and possible moonlighting roles of glucocerebrosidase in Parkinson pathogenesis.

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Section: Discussionmentioning

confidence: 97%

Glucocerebrosidase haploinsufficiency in A53T α-synuclein mice impacts disease onset and course

Tayebi

Parisiadou

Berhe

et al. 2017

Molecular Genetics and Metabolism

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“…A susceptibility of DA neuronal development to the deleterious effects of GBA1 mutations has been reported in some in vivo models of GBA1 deficiency but not in others. Zebrafish with a truncation in the ortholog of human GBA1 display a decrease in motor activity and a reduction in DA neuronal cell count, and this effect is independent from α-synuclein neurotoxicity, as zebrafish lack this gene ( Keatinge et al., 2015 ); similarly, mutations or deletion of GBA1 Drosophila orthologs cause dopaminergic neuronal loss, defective locomotion, and a shorter life span ( Maor et al., 2016 , Sanchez-Martinez et al., 2016 ); however, in a GBA −/− medaka model of neuronopathic GD, the mutant fish exhibited brain infiltration of Gaucher-like cells, microgliosis, and progressive neuronal loss that included but was not limited to TH-positive cells ( Uemura et al., 2015 ); and in mice with a targeted deletion of GBA1 in mature, DAT-expressing midbrain dopaminergic neurons (DAT- GBA1 -KO mice) there was no reduction in the number of TH-positive neurons in the substantia nigra of the mutant mice ( Soria et al., 2017 ). Thus, the effect of GBA1 mutation on DA neuronal numbers and survival seems to be model dependent, and our results using GD iPSC model will need to be validated in future studies.…”

Section: Discussionmentioning

confidence: 99%

Altered Differentiation Potential of Gaucher’s Disease iPSC Neuronal Progenitors due to Wnt/β-Catenin Downregulation

et al. 2017

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SummaryGaucher’s disease (GD) is an autosomal recessive disorder caused by mutations in the GBA1 gene, which encodes acid β-glucocerebrosidase (GCase). Severe GBA1 mutations cause neuropathology that manifests soon after birth, suggesting that GCase deficiency interferes with neuronal development. We found that neuronopathic GD induced pluripotent stem cell (iPSC)-derived neuronal progenitor cells (NPCs) exhibit developmental defects due to downregulation of canonical Wnt/β-catenin signaling and that GD iPSCs’ ability to differentiate to dopaminergic (DA) neurons was strikingly reduced due to early loss of DA progenitors. Incubation of the mutant cells with the Wnt activator CHIR99021 (CHIR) or with recombinant GCase restored Wnt/β-catenin signaling and rescued DA differentiation. We also found that GD NPCs exhibit lysosomal dysfunction, which may be involved in Wnt downregulation by mutant GCase. We conclude that neuronopathic mutations in GCase lead to neurodevelopmental abnormalities due to a critical requirement of this enzyme for canonical Wnt/β-catenin signaling at early stages of neurogenesis.

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“…These results were confirmed by the studies from Rocha et al (2015b) and Mus et al (2019), both showing that a CBE-induced drop in GCase enzymatic activity activates microglia throughout the brain. Interestingly, using a DAT-GBA1-KO mouse displaying selective homozygous GBA1 disruption in midbrain dopamine neurons, Soria et al (2017) demonstrated strong microglial activation in the substantia nigra of these mice, without any evidence of dopaminergic cell loss, alpha-synuclein accumulation, or motor abnormalities.…”

Section: Glucocerebrosidase and Neuroinflammationmentioning

confidence: 99%

“…GCase defects may also contribute to neuroinflammation, a phenomenon that is increasingly implicated in PD pathogenesis, as suggested by various studies demonstrating that a reduction in GCase activity is associated with clear activation of microglia in the brain parenchyma (Ginns et al, 2014;Rocha et al, 2015c;Soria et al, 2017;Mus et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Glucocerebrosidase Defects as a Major Risk Factor for Parkinson’s Disease

Avenali

Blandini

Cerri³

2020

Front. Aging Neurosci.

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Heterozygous mutations of the GBA1 gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), occur in a considerable percentage of all patients with sporadic Parkinson's disease (PD), varying between 8% and 12% across the world. Genome wide association studies have confirmed the strong correlation between PD and GBA1 mutations, pointing to this element as a major risk factor for PD, possibly the most important one after age. The pathobiological mechanisms underlying the link between a defective function of GCase and the development of PD are still unknown and are currently the focus of intense investigation in the community of pre-clinical and clinical researchers in the PD field. A major controversy regards the fact that, despite the unequivocal correlation between the presence of GBA1 mutations and the risk of developing PD, only a minority of asymptomatic carriers with GBA1 mutations convert to PD in their lifetime. GBA1 mutations reduce the enzymatic function of GCase, impairing lysosomal efficiency and the cellular ability to dispose of pathological alpha-synuclein. Changes in the cellular lipidic content resulting from the accumulation of glycosphingolipids, triggered by lysosomal dysfunction, may contribute to the pathological modification of alpha-synuclein, due to its ability to interact with cell membrane lipids. Mutant GCase can impair mitochondrial function and cause endoplasmic reticulum stress, thereby impacting on cellular energy production and proteostasis. Importantly, reduced GCase activity is associated with clear activation of microglia, a major mediator of neuroinflammatory response within the brain parenchyma, which points to neuroinflammation as a major consequence of GCase dysfunction. In this present review article, we summarize the current knowledge on the role of GBA1 mutations in PD development and their phenotypic correlations. We also discuss the potential role of the GCase pathway in the search for PD biomarkers that may enable the development of disease modifying therapies. Answering these questions will aid clinicians in offering more appropriate counseling to the patients and their caregivers and provide future directions for PD preclinical research.

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Glucocerebrosidase deficiency in dopaminergic neurons induces microglial activation without neurodegeneration

Cited by 36 publications

References 53 publications

Glucocerebrosidase haploinsufficiency in A53T α-synuclein mice impacts disease onset and course

Glucocerebrosidase haploinsufficiency in A53T α-synuclein mice impacts disease onset and course

Altered Differentiation Potential of Gaucher’s Disease iPSC Neuronal Progenitors due to Wnt/β-Catenin Downregulation

Glucocerebrosidase Defects as a Major Risk Factor for Parkinson’s Disease

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