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Calpain-Inhibitors Protect Frataxin-Deficient Dorsal Root Ganglia Neurons from Loss of Mitochondrial Na+/Ca2+ Exchanger, NCLX, and Apoptosis

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Abstract

Calpains are calcium-dependent proteases activated in apoptotic cell death and neurodegeneration. Friedreich Ataxia is a neurodegenerative rare disease caused by frataxin deficiency, a mitochondrial protein. Dorsal root ganglion (DRG) sensory neurons are among the cellular types most affected in this disease. We have previously demonstrated that frataxin-deficient DRGs show calpain activation, alteration in calcium levels and decreased content of the Na+/Ca2+ exchanger (NCLX). This transporter is involved in mitochondrial calcium efflux. In this study, we have performed a time-course analysis of several parameters altered in a frataxin-deficient DRGs. These include decline of NCLX levels, calcium accumulation, mitochondrial depolarization, α-fodrin fragmentation and apoptotic cell death. Furthermore, we have analysed the effect of the calpain inhibitors MDL28170 and Calpeptin on these parameters. We have observed that these inhibitors increase NCLX levels, protect sensory neurons from neurite degeneration and calcium accumulation, and restore mitochondrial membrane potential. In addition, calpain 1 reduction alleviated neurodegeneration in frataxin-deficient DRG neurons. These results strengthen the hypothesis of a central role for calcium homeostasis and calpains in frataxin-deficient dorsal root ganglia neurons.

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Acknowledgements

This work has been funded by Project SAF2017-83883-R from MINECO (Spain), the Juan de la Cierva Incorporación postdoctoral fellowship to FD. We thank Arabela Sanz for helping with DRG isolation and processing and Roser Pané for technical assistance. We are indebted to R. Soler lab for kindly supplying lentivirus carrying shCALP1 and EV and for Calpain 1 antibody.

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  1. Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, Lleida, Spain

    Elena Britti, Fabien Delaspre, Jordi Tamarit & Joaquim Ros

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  1. Elena Britti
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  2. Fabien Delaspre
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  3. Jordi Tamarit
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  4. Joaquim Ros
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Correspondence to Joaquim Ros.

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Britti, E., Delaspre, F., Tamarit, J. et al. Calpain-Inhibitors Protect Frataxin-Deficient Dorsal Root Ganglia Neurons from Loss of Mitochondrial Na+/Ca2+ Exchanger, NCLX, and Apoptosis. Neurochem Res 46, 108–119 (2021). https://doi.org/10.1007/s11064-020-03020-3

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