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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / drug effects*
  • Axons / metabolism
  • Axons / pathology
  • Calcium Signaling / drug effects
  • Cell Line
  • Disease Models, Animal
  • Friedreich Ataxia / metabolism
  • Friedreich Ataxia / pathology*
  • Ganglia, Spinal / drug effects*
  • Ganglia, Spinal / metabolism
  • Ganglia, Spinal / pathology
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Phosphodiesterase Inhibitors / pharmacology*
  • Proteomics
  • Sensory Receptor Cells / drug effects*
  • Sensory Receptor Cells / metabolism
  • Sensory Receptor Cells / pathology


  • Phosphodiesterase Inhibitors