Apoptotic cell death and altered calcium homeostasis caused by frataxin depletion in dorsal root ganglia neurons can be prevented by BH4 domain of Bcl-xL protein

Tasheva, Stefka Mincheva; Obis Monné, Èlia; Tamarit Sumalla, Jordi; Ros Salvador, Joaquim

doi:https://doi.org/10.1093/hmg/ddt576

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Issue date

2014

Author

Tasheva, Stefka Mincheva

Obis Monné, Èlia

Tamarit Sumalla, Jordi

Ros Salvador, Joaquim

Suggested citation

Tasheva, Stefka Mincheva; Obis Monné, Èlia; Tamarit Sumalla, Jordi; Ros Salvador, Joaquim; . (2014) . Apoptotic cell death and altered calcium homeostasis caused by frataxin depletion in dorsal root ganglia neurons can be prevented by BH4 domain of Bcl-xL protein. Human Molecular Genetics, 2014, vol. 23, núm. 7, p. 1829-1841. https://doi.org/10.1093/hmg/ddt576.

Abstract

Friedreich ataxia (FRDA) is a neurodegenerative disease characterized by a decreased expression of the mitochondrial protein frataxin. Major neurological symptoms of the disease are due to degeneration of dorsal root ganglion (DRG) sensory neurons. In this studywe have explored the neurodegenerative events occurring by frataxin depletion on primary cultures of neurons obtained from rat DRGs. Reduction of 80% of frataxin levels in these cellswasachievedbytransduction with lentivirus containingshRNAsilencing sequences. Frataxin depletion caused mitochondrial membrane potential decrease, neurite degeneration and apoptotic cell death. A marked increase of free intracellular Ca21 levels and alteration in Ca21-mediated signaling pathways was also observed, thus suggesting that altered calcium homeostasis can play a pivotal role in neurodegeneration caused by frataxin deficiency. These deleterious effects were reverted by the addition of a cell-penetrant TAT peptidecoupled to theBH4,the anti-apoptoticdomainof Bcl-xL. Treatmentof cultured frataxin-depletedneurons with TAT-BH4 was able to restore the free intracellular Ca21 levels and protect the neurons from degeneration. These observations open the possibility of new therapies of FRDA based on modulating the Ca21 signaling and prevent apoptotic process to protect DRG neurons from neurodegeneration.

URI

http://hdl.handle.net/10459.1/57124

DOI

https://doi.org/10.1093/hmg/ddt576

Is part of

Human Molecular Genetics, 2014, vol. 23, núm. 7, p. 1829-1841