Impaired neuromuscular transmission and skeletal muscle fiber necrosis in mice lacking Na/Ca exchanger 3

Sokolow, Sophie; Manto, Mario; Gailly, Philippe; Molgó, Jordi; Vandebrouck, Clarisse; Vanderwinden, Jean‐Marie; Herchuelz, André; Schurmans, Stéphane

doi:10.1172/jci18688

Cited by 75 publications

(53 citation statements)

References 34 publications

(16 reference statements)

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“…Indeed, BHK-WT cells do not constitutively expressed any NCX isoform, BHK-NCX3 cells are genetic engineered cells to solely expressed NCX3-specific brain isoform whereas wild-type VMC neurons express NCX1, NCX2 and NCX3 isoforms (Canitano, 2002, Linck, 1998, Minelli, 2007, Nicoll, 1996, Sokolow, 2011). Due to the lack of selective NCX3 inhibitor, we opted to investigate the role of ziram induced DA toxicity in VMC neurons isolated from NCX3 knock-out mice (Molinaro, 2008, Molinaro, 2011, Pannaccione, 2012, Sokolow, 2004). …”

Section: Resultsmentioning

confidence: 99%

“…NCX3 −/− mice were generated by inserting a neomycin resistance cassette (neo) into the exon 2 of NCX3 gene (Sokolow, 2004). NCX3 −/− mice were backcrossed against C57/Bl6 background for a minimum of 6 generations (Molinaro, 2008).…”

Section: Methodsmentioning

confidence: 99%

“…NCX1 is most abundant in the heart and is widely distributed in excitable cells (Minelli et al, 2007, Thurneysen et al, 2002). NCX2 expression is restricted to the brain and spinal cord (Jeon et al, 2003, Minelli, 2007), while NCX3 expression is limited to the central nervous system and skeletal muscle (Minelli, 2007, Sokolow et al, 2004). In situ hybridization experiments in rodent brain showed that NCX1, NCX2 and NCX3 mRNA are distributed in all brain regions including the substantia nigra (SNc), a region primarily affected in PD (Canitano et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Involvement of the sodium–calcium exchanger 3 (NCX3) in ziram-induced calcium dysregulation and toxicity

et al. 2014

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Ziram is a dimethyldithiocarbamate fungicide which can cause intraneuronal calcium (Ca2+) dysregulation and subsequently neuronal death. The signaling mechanisms underlying ziram-induced Ca2+ dyshomeostasis and neurotoxicity are not fully understood. NCX3 is the third isoform of the sodium-calcium exchanger (NCX) family and plays an important role in regulating Ca2+ homeostasis in excitable cells. We previously generated a mouse model deficient for the sodium-calcium exchanger 3 and showed that NCX3 is protective against ischemic damage. In the present study, we aim to examine whether NCX3 exerts a similar role against toxicological injury caused by the pesticide ziram. Our data show baby hamster kidney (BHK) cells stably transfected with NCX3 (BHK-NCX3) are more susceptible to ziram toxicity than cells transfected with the empty vector (BHK-WT). Increased toxicity in BHK-NCX3 was associated with a rapid rise in cytosolic Ca2+ concentration [Ca2+i] induced by ziram. Profound mitochondrial dysfunction and ATP depletion were also observed in BHK-NCX3 cells following treatment with ziram. Lastly, primary dopaminergic neurons lacking NCX3 (NCX3−/−) were less sensitive to ziram neurotoxicity than wildtype control dopaminergic neurons. These results demonstrate that NCX3 genetic deletion protects against ziram-induced neurotoxicity and suggest NCX3 and its downstream molecular pathways as key factors involved in ziram toxicity. Our study identifies new molecular events through which pesticides (e.g. ziram) can lead to pathological features of degenerative diseases such as Parkinson’s disease and indicates new targets to slow down neuronal degeneration.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Involvement of the sodium–calcium exchanger 3 (NCX3) in ziram-induced calcium dysregulation and toxicity

et al. 2014

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“…NCX2 expression is restricted to the brain and spinal cord [11]. NCX3 expression is restricted to the brain and skeletal muscle [12–13]. In the neocortex and hippocampus, NCX isoforms are widely distributed and are expressed in neurons, astrocytes, oligodendrocytes and capillary endothelial cells [7, 14–16].…”

Section: Introductionmentioning

confidence: 99%

“…NCX1-, NCX2- and NCX3- specific knockout mice were generated over the past decade [11–12, 19]. These mouse models are useful tools for elucidating NCX1-3 specific function in physiological and pathophysiological processes in the central nervous system.…”

Section: Introductionmentioning

confidence: 99%

High levels of synaptosomal Na+–Ca2+ exchangers (NCX1, NCX2, NCX3) co-localized with amyloid-beta in human cerebral cortex affected by Alzheimer's disease

et al. 2011

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Synaptosomal expression of NCX1, NCX2, and NCX3, the three variants of the Na+-Ca2+ exchanger (NCX), was investigated in Alzheimer’s disease parietal cortex. Flow cytometry and immunoblotting techniques were used to analyze synaptosomes prepared from cryopreserved brain of cognitively normal aged controls and late stage Alzheimer’s disease patients. Major findings that emerged from this study are: (1) NCX1 was the most abundant NCX isoform in nerve terminals of cognitively normal patients; (2) NCX2 and NCX3 protein levels were modulated in parietal cortex of late stage Alzheimer’s disease: NCX2 positive terminals were increased in the Alzheimer’s disease cohort while counts of NCX3 positive terminals were reduced; (3) NCX1, NCX2 and NCX3 isoforms co-localized with amyloid-beta in synaptic terminals and all three variants are up-regulated in nerve terminals containing amyloid-beta. Taken together, these data indicate that NCX isoforms are selectively regulated in pathological terminals, suggesting different roles of each NCX isoform in Alzheimer’s disease terminals.

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Myofiber Damage Evaluation by Evans Blue Dye Injection

Wooddell¹,

Radley‐Crabb

Griffin³

2011

CP Mouse Biology

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Evans blue dye (EBD) can be used in live mice to study muscle pathology or injury, including exercise-induced muscle damage. EBD is excluded from intact cell membranes but leaks into cells, including muscle fibers, when the cell membrane is ruptured. EBD can be visualized by its autofluorescence under a fluorescence microscope. EBD-stained myofibers can be quantified from microscope images of muscle cross-sections. These myofibers are often in clusters that lend themselves to morphometric analysis. When the damaged myofibers are interspersed among intact myofibers, however, a more suitable approach is to count individual myofibers in the field of view. A much faster approach to measure EBD in muscles from different strains of mice or between treatment groups is to extract the EBD from muscle samples and quantitate it using a spectrophotometric microplate reader. The advantages and disadvantages of using each of these approaches are discussed here. Curr. Protoc. Mouse Biol. 1:463-488 © 2011 by John Wiley & Sons, Inc.

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Impaired neuromuscular transmission and skeletal muscle fiber necrosis in mice lacking Na/Ca exchanger 3

Cited by 75 publications

References 34 publications

Involvement of the sodium–calcium exchanger 3 (NCX3) in ziram-induced calcium dysregulation and toxicity

Involvement of the sodium–calcium exchanger 3 (NCX3) in ziram-induced calcium dysregulation and toxicity

High levels of synaptosomal Na+–Ca2+ exchangers (NCX1, NCX2, NCX3) co-localized with amyloid-beta in human cerebral cortex affected by Alzheimer's disease

Myofiber Damage Evaluation by Evans Blue Dye Injection

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