Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload

Plotegher, Nicoletta; Perocheau, Dany; Ferrazza, Ruggero; Massaro, Giulia; Bhosale, Gauri; Zambon, Federico; Rahim, Afidah Abdul; Guella, Graziano; Waddington, Simon N.; Szabadkai, György; Duchen, Michael R.

doi:10.1038/s41418-019-0442-2

Cited by 28 publications

(25 citation statements)

References 60 publications

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“…A global pseudohypoxia, of course, would be also expected to be a proximate cause of neurological dysfunction (since neurons are highly ATP-dependent cells, highly susceptible to disturbances in cellular bioenergetic processes) (Hoyer 1990 ; Zeiger et al 2011 ; Funes et al 2014 ; Nicholls et al 2015 ; Hebert-Chatelain et al 2016 ; Plotegher et al 2020 ). We hypothesize that neuronal pseudohypoxia may also potentially contribute to the process of delayed neurodegeneration (Alzheimer-like symptoms) in DS.…”

Section: Implications Conclusion and Outlookmentioning

confidence: 99%

Meta-analysis of metabolites involved in bioenergetic pathways reveals a pseudohypoxic state in Down syndrome

Pecze

Randi

Szabó

2020

Mol Med

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Clinical observations and preclinical studies both suggest that Down syndrome (DS) may be associated with significant metabolic and bioenergetic alterations. However, the relevant scientific literature has not yet been systematically reviewed. The aim of the current study was to conduct a meta-analysis of metabolites involved in bioenergetics pathways in DS to conclusively determine the difference between DS and control subjects. We discuss these findings and their potential relevance in the context of pathogenesis and experimental therapy of DS. Articles published before July 1, 2020, were identified by using the search terms “Down syndrome” and “metabolite name” or “trisomy 21” and “metabolite name”. Moreover, DS-related metabolomics studies and bioenergetics literature were also reviewed. 41 published reports and associated databases were identified, from which the descriptive information and the relevant metabolomic parameters were extracted and analyzed. Mixed effect model revealed the following changes in DS: significantly decreased ATP, CoQ10, homocysteine, serine, arginine and tyrosine; slightly decreased ADP; significantly increased uric acid, succinate, lactate and cysteine; slightly increased phosphate, pyruvate and citrate. However, the concentrations of AMP, 2,3-diphosphoglycerate, glucose, and glutamine were comparable in the DS vs. control populations. We conclude that cells of subjects with DS are in a pseudo-hypoxic state: the cellular metabolic and bio-energetic mechanisms exhibit pathophysiological alterations that resemble the cellular responses associated with hypoxia, even though the supply of the cells with oxygen is not disrupted. This fundamental alteration may be, at least in part, responsible for a variety of functional deficits associated with DS, including reduced exercise difference, impaired neurocognitive status and neurodegeneration.

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Section: Implications Conclusion and Outlookmentioning

confidence: 99%

Meta-analysis of metabolites involved in bioenergetic pathways reveals a pseudohypoxic state in Down syndrome

Pecze

Randi

Szabó

2020

Mol Med

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“…We show in the present study that these glucosylceramides are increased in the DRGs of Pink1SNCA mice strengthening the idea that they contribute to the pathology of sensory neurons. Mutations of GBA1, the key lysosomal enzyme catalyzing GlcCer degradation, have been associated with autophagolysosmal dysfunctions [66,67], increased alpha-synuclein toxicity [27,68] and disruptions of mitochondrial energy production [49]. GBA1 expression was unaltered in the DRGs of Pink1SNCA mice, and the ultrastructural morphology of lysosomes and lipid droplets in DRG neurons appeared to be normal for the age.…”

Section: Discussionmentioning

confidence: 99%

“…So far, most studies addressing the functional consequences of GBA1 deletion assumed that the observed pathology was caused by glucosylceramides without directly measuring these lipids. GBA1 deletion or mutation increased alpha-synuclein aggregates [26,27], led to mitochondrial calcium overload [49], ER stress [69] and disruption of autophagolysosomal pathways [67].…”

Section: Discussionmentioning

confidence: 99%

“…Intracellular accumulation of GlcCer owing to GBA1 mutations are supposed to interfere with mitochondrial functions and autophagolysosomal removal of damaged mitochondria via mitophagy [48,49]. Using oxygraph respirometry, we measured cellular oxygen consumption and OXPHOS activity with 'substrate-uncoupler-inhibitor' titration protocols in freshly prepared tissue of the prefrontal cortex, hippocampus and of sensory ganglia (DRGs and trigeminal ganglia) in 18 months old Pink1SNCA versus wildtype control mice ( Fig.…”

Section: Reduction Of Oxygen Consumption Of Sensory Neurons Pointing mentioning

confidence: 99%

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Early prodromal sensory neuropathy in Pink1-SNCA double mutant Parkinson mice

Valek¹,

Tran²,

Wilken-Schmitz³

et al. 2020

Preprint

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BACKGROUND: Parkinson's Disease (PD) is frequently associated with a prodromal sensory neuropathy, which manifests as sensory loss and eventually chronic pain. METHODS: The present study assessed somatosensory functions and the pathology of somatosensory neurons in Pink1-/-SNCAA53T double mutant mice (Pink1SNCA) who develop a PD-like disease > 15 months of age. RESULTS: Pink1SNCA mice showed the first manifestations of sensory dysfunctions at 6 months of age, which were characterized by a loss of thermal sensitivity but sparing of mechanical sensation, and decline of olfactory perception of pleasant odors. Mechanistically, the loss of thermal sensitivity was attributed to a strong reduction of transient receptor potential TRPV and TRPA channels at mRNA, protein and functional levels in the dorsal root ganglia (DRGs). Primary sensory neurons responded much less to stimulations with capsaicin, formalin or depolarization as assessed by calcium imaging. RNA sequencing pointed to additional deregulations of voltage dependent potassium channel subtypes, lowering of acidic fibroblast growth factor driven support, and alterations of sphingolipid metabolism. Analyses of sphingolipids of multiple classes revealed an accumulation of glucosylceramides mainly in the DRGs and loss of sphingosines and sphinganines in the sciatic nerve. Transmission electron microscopy of the DRGs revealed a higher frequency of neurons with swollen mitochondria, which was associated with a decrease of mitochondrial respiration in sensory ganglia, but not in the brain. CONCLUSION: The data support the view of a prodromal sensory disease in PD resulting from a combination of lipid allostasis and mitochondrial damage. Hence, Pink1SNCA mice phenocopy the PD-associated prodromal sensory neuropathy and reveal novel mechanistic insight.

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“…A growing number of studies have found that the Glu is closely associated with the etiology and pathology of many neurological and psychiatric disorders, such as cerebral ischemia, epilepsy, Alzheimer's disease, Huntington's disease, schizophrenia, and Pico disease [14]. Oxidative stress caused by Glu is an important cause of neurodegenerative diseases [15,16], high concentration of Glu inhibits cysteine/glutamate antiporter or system x-CT in neuronal cells, causes calcium overload that interferes with mitochondrial respiratory chain function, thereby inhibiting cystine uptake and causing intracellular glutathione (GSH) deprivation and ROS accumulation, and ultimately leading to cell necrosis or apoptosis [17,18]. Moreover, studies have shown that the caspase-dependent apoptotic pathway is related with Glu-neurotoxicity [19].…”

Section: Introductionmentioning

confidence: 99%

Tetrastigma hemsleyanum Vine Flavone Ameliorates Glutamic Acid-Induced Neurotoxicity via MAPK Pathways

Chu

Zheng

et al. 2020

Oxidative Medicine and Cellular Longevity

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Glutamic acid (Glu) is a worldwide flavor enhancer with various positive effects. However, Glu-induced neurotoxicity has been reported less. Tetrastigma hemsleyanum (TH), a rare herbal plant in China, possesses high medicinal value. More studies paid attention to tuber of TH whereas vine part (THV) attracts fewer focus. In this study, we extracted and purified flavones from THV (THVF), and UPLC-TOF/MS showed THVF was consisted of 3-caffeoylquinic acid, 5-caffeoylquinic acid, quercetin-3-O-rutinoside, and kaempferol-3-O-rutinoside. In vitro, Glu caused severe cytotoxicity, genotoxicity, mitochondrial dysfunction, and oxidative damage to rat phaeochromocytoma (PC12) cells. Conversely, THVF attenuated Glu-induced toxicity via MAPK pathways. In vivo, the neurotoxicity triggered by Glu restrained the athletic ability in Caenorhabditis elegans (C. elegans). The treatment of THVF reversed the situation induced by Glu. In a word, Glu could cause neurotoxicity and THVF owns potential neuroprotective effects both in vitro and in vivo via MAPK pathways.

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Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload

Cited by 28 publications

References 60 publications

Meta-analysis of metabolites involved in bioenergetic pathways reveals a pseudohypoxic state in Down syndrome

Meta-analysis of metabolites involved in bioenergetic pathways reveals a pseudohypoxic state in Down syndrome

Early prodromal sensory neuropathy in Pink1-SNCA double mutant Parkinson mice

Tetrastigma hemsleyanum Vine Flavone Ameliorates Glutamic Acid-Induced Neurotoxicity via MAPK Pathways

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