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Gene Transfer of Brain-derived Neurotrophic Factor (BDNF) Prevents Neurodegeneration Triggered by FXN Deficiency.
- Source :
-
Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2016 May; Vol. 24 (5), pp. 877-89. Date of Electronic Publication: 2016 Feb 05. - Publication Year :
- 2016
-
Abstract
- Friedreich's ataxia is a predominantly neurodegenerative disease caused by recessive mutations that produce a deficiency of frataxin (FXN). Here, we have used a herpesviral amplicon vector carrying a gene encoding for brain-derived neurotrophic factor (BDNF) to drive its overexpression in neuronal cells and test for its effect on FXN-deficient neurons both in culture and in the mouse cerebellum in vivo. Gene transfer of BDNF to primary cultures of mouse neurons prevents the apoptosis which is triggered by the knockdown of FXN gene expression. This neuroprotective effect of BDNF is also observed in vivo in a viral vector-based knockdown mouse cerebellar model. The injection of a lentiviral vector carrying a minigene encoding for a FXN-specific short hairpin ribonucleic acid (shRNA) into the mouse cerebellar cortex triggers a FXN deficit which is accompanied by significant apoptosis of granule neurons as well as loss of calbindin in Purkinje cells. These pathological changes are accompanied by a loss of motor coordination of mice as assayed by the rota-rod test. Coinjection of a herpesviral vector encoding for BDNF efficiently prevents both the development of cerebellar neuropathology and the ataxic phenotype. These data demonstrate the potential therapeutic usefulness of neurotrophins like BDNF to protect FXN-deficient neurons from degeneration.
- Subjects :
- Animals
Apoptosis drug effects
Brain-Derived Neurotrophic Factor metabolism
Cells, Cultured
Disease Models, Animal
Friedreich Ataxia genetics
Gene Knockdown Techniques
Genetic Vectors administration & dosage
Herpesviridae genetics
Humans
Mice
Neurons drug effects
Frataxin
Brain-Derived Neurotrophic Factor genetics
Friedreich Ataxia prevention & control
Genetic Therapy methods
Iron-Binding Proteins genetics
Neurons pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1525-0024
- Volume :
- 24
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Molecular therapy : the journal of the American Society of Gene Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 26849417
- Full Text :
- https://doi.org/10.1038/mt.2016.32