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
Issue date
2014Suggested 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.
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Show full item recordAbstract
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.
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Human Molecular Genetics, 2014, vol. 23, núm. 7, p. 1829-1841European research projects
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