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Na+/Ca2+ exchanger isoform 1 takes part to the Ca2+-related prosurvival pathway of SOD1 in primary motor neurons exposed to beta-methylamino-l-alanine.
- Source :
- Cell Communication & Signaling; 1/12/2022, Vol. 20 Issue 1, p1-12, 12p
- Publication Year :
- 2022
-
Abstract
- Background: The cycad neurotoxin beta-methylamino-l-alanine (L-BMAA), one of the environmental trigger factor for amyotrophic lateral sclerosis/Parkinson-dementia complex (ALS/PDC), may cause neurodegeneration by disrupting organellar Ca<superscript>2+</superscript> homeostasis. Through the activation of Akt/ERK1/2 pathway, the Cu,Zn-superoxide dismutase (SOD1) and its non-metallated form, ApoSOD1, prevent endoplasmic reticulum (ER) stress-induced cell death in motor neurons exposed to L-BMAA. This occurs through the rapid increase of intracellular Ca<superscript>2+</superscript> concentration ([Ca<superscript>2+</superscript>]<subscript>i</subscript>) in part flowing from the extracellular compartment and in part released from ER. However, the molecular components of this mechanism remain uncharacterized. Methods: By an integrated approach consisting on the use of siRNA strategy, Western blotting, confocal double- labeling immunofluorescence, patch-clamp electrophysiology, and Fura 2-/SBFI-single-cell imaging, we explored in rat motor neuron-enriched cultures the involvement of the plasma membrane proteins Na<superscript>+</superscript>/Ca<superscript>2+</superscript> exchanger (NCX) and purinergic P<subscript>2</subscript>X<subscript>7</subscript> receptor as well as that of the intracellular cADP-ribose (cADPR) pathway, in the neuroprotective mechanism of SOD1. Results: We showed that SOD1-induced [Ca<superscript>2+</superscript>]<subscript>i</subscript> rise was prevented neither by A430879, a P<subscript>2</subscript>X<subscript>7</subscript> receptor specific antagonist or 8-bromo-cADPR, a cell permeant antagonist of cADP-ribose, but only by the pan inhibitor of NCX, CB-DMB. The same occurred for the ApoSOD1. Confocal double labeling immunofluorescence showed a huge expression of plasmalemmal NCX1 and intracellular NCX3 isoforms. Furthermore, we identified NCX1 reverse mode as the main mechanism responsible for the neuroprotective ER Ca<superscript>2+</superscript> refilling elicited by SOD1 and ApoSOD1 through which they promoted translocation of active Akt in the nuclei of a subset of primary motor neurons. Finally, the activation of NCX1 by the specific agonist CN-PYB2 protected motor neurons from L-BMAA-induced cell death, mimicking the effect of SOD1. Conclusion: Collectively, our data indicate that SOD1 and ApoSOD1 exert their neuroprotective effect by modulating ER Ca<superscript>2+</superscript> content through the activation of NCX1 reverse mode and Akt nuclear translocation in a subset of primary motor neurons. 7n_RSb6LJnzKN1GMcoyFaw Video Abstract [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 1478811X
- Volume :
- 20
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Cell Communication & Signaling
- Publication Type :
- Academic Journal
- Accession number :
- 154662363
- Full Text :
- https://doi.org/10.1186/s12964-021-00813-z