A major feature of FRDA is frataxin deficiency, with the loss of large sensory neurons of the dorsal root ganglia (DRG) undergoing dying-back neurodegeneration. This group used isolated DRGs from a FRDA mouse model and control mice for a proteomic study and a primary culture of sensory neurons from DRG to test novel pharmacological strategies. They found a decreased expression of electron transport chain proteins, the oxidative phosphorylation 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 . 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 from YG8R mice. This suggests that PDE inhibitors should be looked at as a future FRDA treatment.

Read the entire article HERE