Gene Transfer of Brain-derived Neurotrophic Factor (BDNF) Prevents Neurodegeneration Triggered by FXN Deficiency

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.

A Comprehensive Transcriptome Analysis Identifies FXN and BDNF as Novel Targets of miRNAs in Friedreich’s Ataxia Patients

“…Expression of the BDNF gene is reduced in patients with several neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's disease [38][39][40]. Importantly, gene transfer of BDNF into both primary neurons and a mouse model of FRDA impeded neurodegeneration, underscoring the importance of BDNF in this process [55]. In addition, regulation of BDNF expression levels by miRNA-10a-5p has been reported previously in granulosa cells of the ovary [56] and cervical cancer cells [45]; this miRNA was also differentially expressed in the cerebrospinal fluid of Alzheimer's and Parkinson's disease patients [57] as well as in brain tissue samples from Huntington's disease patients [58].…”

Peptide selected by phage display increases survival of SH‐SY5Y neurons comparable to brain‐derived neurotrophic factor

“…20,44,45 However, none of these peptidomimetics could mimic BDNF function completely. 21 A novel artificial NTRK2 agonist, BM17d99, was recently identified by Ohnishi et al 46 using T7 phagedisplayed random peptide libraries. The T7Select 10-3b cloning system may produce a population of phages that do not display the random peptide encoded in the phage genome.…”

The Causative and Curative Roles of Brain-Derived Neurotrophic Factor in Parkinson’s Disease

“…In brain, BDNF not only mediates region-specific effects on synaptic function and neuronal morphology [8] but is also involved in various functions including aging [101], anxiety [102], chronic pain [103], deafness [104], depression [105] and long-term memory storage [9]. BDNF is proven to be the best therapeutic gene for treating metabolic syndrome [106], Friedreich's ataxia [107], neuropsychiatric or neurocognitive disorders [108], brain ischemia [109], schizophrenia [110], glaucoma [111], epilepsy [112], spinocerebellar ataxia typ. 6 [113], Huntington's disease [21], multiple sclerosis [114], amyotrophic lateral sclerosis [115], spinal cord injury [116], Alzheimer's disease [22] and PD [117].…”