Format

Send to

Choose Destination
Neurotherapeutics. 2019 Apr;16(2):432-449. doi: 10.1007/s13311-018-00706-z.

Phosphodiesterase Inhibitors Revert Axonal Dystrophy in Friedreich's Ataxia Mouse Model.

Author information

1
CIBER de Enfermedades Raras (CIBERER), Valencia, 46010, Spain.
2
Instituto de Biomedicina de Valencia (IBV), CSIC, 46010, Valencia, Spain.
3
Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Avda. Blasco Ibañez, 46010, Valencia, Spain.
4
Associated Unit for Rare Diseases INCLIVA-CIPF, Valencia, 46010, Spain.
5
Department of Genetics, University of Valencia, Campus of Burjassot, 46100, Valencia, Spain.
6
Brain Connectivity Laboratory, Joint Unit FISABIO & Prince Felipe Research Centre (CIPF), 46012, Valencia, Spain.
7
Regional Ministry of Health in Valencia, Hospital Sagunto (CEIB-CSUSP), Valencia, 46500, Spain.
8
CIBER de Salud Mental (CIBERSAM), Valencia, 46010, Spain.
9
Biomedical Research Institute INCLIVA, 46010, Valencia, Spain.
10
Institut de Recerca Sant Joan de Déu and Department of Genetic & Molecular Medicine and IPER, Hospital Sant Joan de Déu, 08950, Barcelona, Spain.
11
Department of Pediatrics, University of Barcelona School of Medicine, Barcelona, 08036, Spain.
12
CIBER de Enfermedades Raras (CIBERER), Valencia, 46010, Spain. pilargc@uv.es.
13
Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Avda. Blasco Ibañez, 46010, Valencia, Spain. pilargc@uv.es.
14
Associated Unit for Rare Diseases INCLIVA-CIPF, Valencia, 46010, Spain. pilargc@uv.es.
15
Biomedical Research Institute INCLIVA, 46010, Valencia, Spain. pilargc@uv.es.

Abstract

Friedreich's ataxia (FRDA) is a neurodegenerative disorder caused by an unstable GAA repeat expansion within intron 1 of the FXN gene and characterized by peripheral neuropathy. A major feature of FRDA is frataxin deficiency with the loss of large sensory neurons of the dorsal root ganglia (DRG), namely proprioceptive neurons, undergoing dying-back neurodegeneration with progression to posterior columns of the spinal cord and cerebellar ataxia. We used isolated DRGs from a YG8R FRDA mouse model and C57BL/6J control mice for a proteomic study and a primary culture of sensory neurons from DRG to test novel pharmacological strategies. We found a decreased expression of electron transport chain (ETC) proteins, the oxidative phosphorylation (OXPHOS) system and antioxidant enzymes, confirming a clear impairment in mitochondrial function and an oxidative stress-prone phenotype. The proteomic profile also showed a decreased expression in Ca2+ signaling related proteins and G protein-coupled receptors (GPCRs). These receptors modulate intracellular cAMP/cGMP and Ca2+ levels. Treatment of frataxin-deficient sensory neurons with phosphodiesterase (PDE) inhibitors was able to restore improper cytosolic Ca2+ levels and revert the axonal dystrophy found in DRG neurons of YG8R mice. In conclusion, the present study shows the effectiveness of PDE inhibitors against axonal degeneration of sensory neurons in YG8R mice. Our findings indicate that PDE inhibitors may become a future FRDA pharmacological treatment.

KEYWORDS:

Ca2+ signaling; FRDA; G protein-coupled receptor (GPCR); PDE inhibitors; axonal degeneration

PMID:
30761510
PMCID:
PMC6554462
[Available on 2020-04-01]
DOI:
10.1007/s13311-018-00706-z

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center