Phosphodiesterase Inhibitors Revert Axonal Dystrophy in Friedreich’s Ataxia Mouse Model

  • Belén Mollá
  • Diana C. Muñoz-Lasso
  • Pablo Calap
  • Angel Fernandez-Vilata
  • María de la Iglesia-Vaya
  • Federico V. Pallardó
  • Maria Dolores Moltó
  • Francesc Palau
  • Pilar Gonzalez-CaboEmail author
Original Article


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.

Key Words

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



This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (Grant No. PI11/00678; SAF2015-66625-R) within the framework of the National R + D + I Plan and cofunded by the Instituto de Salud Carlos III (ISCIII)-Subdirección General de Evaluación y Fomento de la Investigación and FEDER funds, Fundación Ramón Areces (CIVP18A3899), and the Generalitat Valenciana (PROMETEOII/2014/067, PROMETEOII/2014/029, ACIF/2014/090, ACOMP/2014/058). CIBERER is an initiative developed by the Instituto de Salud Carlos III in cooperative and translational research on rare diseases. We would like to thank the staff of the CIBERER Biobank (Valencia, Spain) for their help in generating the lymphoblastoid cell lines (LCLs).

Authors’ Contributions

BM conducted and designed experiments, analyzed the results, and wrote the manuscript. DM and PC performed experiments. MI and AF customized mito-morphology macro of ImageJ for morphometric mitochondrial analysis. FVP and MDM interpreted the data and wrote the manuscript. FP and PG designed the study, supervised the experiments, analyzed the data, and wrote the manuscript. All authors read and approved the final manuscript.

Compliance with Ethical Standards

Competing Interests

The authors declare that they have no competing interests.

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Disclosure forms provided by the authors are available with the online version of this article.

Supplementary material

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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2019

Authors and Affiliations

  • Belén Mollá
    • 1
    • 2
  • Diana C. Muñoz-Lasso
    • 3
    • 4
  • Pablo Calap
    • 1
    • 3
    • 4
    • 5
  • Angel Fernandez-Vilata
    • 6
  • María de la Iglesia-Vaya
    • 6
    • 7
    • 8
  • Federico V. Pallardó
    • 1
    • 3
    • 4
    • 9
  • Maria Dolores Moltó
    • 5
    • 8
    • 9
  • Francesc Palau
    • 1
    • 10
    • 11
  • Pilar Gonzalez-Cabo
    • 1
    • 3
    • 4
    • 9
    Email author
  1. 1.CIBER de Enfermedades Raras (CIBERER)ValenciaSpain
  2. 2.Instituto de Biomedicina de Valencia (IBV), CSICValenciaSpain
  3. 3.Department of Physiology, Faculty of Medicine and DentistryUniversity of ValenciaValenciaSpain
  4. 4.Associated Unit for Rare Diseases INCLIVA-CIPFValenciaSpain
  5. 5.Department of GeneticsUniversity of Valencia, Campus of BurjassotValenciaSpain
  6. 6.Brain Connectivity Laboratory, Joint Unit FISABIO & Prince Felipe Research Centre (CIPF)ValenciaSpain
  7. 7.Regional Ministry of Health in ValenciaHospital Sagunto (CEIB-CSUSP)ValenciaSpain
  8. 8.CIBER de Salud Mental (CIBERSAM)ValenciaSpain
  9. 9.Biomedical Research Institute INCLIVAValenciaSpain
  10. 10.Institut de Recerca Sant Joan de Déu and Department of Genetic & Molecular Medicine and IPERHospital Sant Joan de DéuBarcelonaSpain
  11. 11.Department of PediatricsUniversity of Barcelona School of MedicineBarcelonaSpain

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