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

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 Ca 2+ signaling related proteins and G protein-coupled receptors (GPCRs). These receptors modulate intracellular cAMP/cGMP and Ca 2+ levels. Treatment of frataxin-deficient sensory neurons with phosphodiesterase (PDE) inhibitors was able to restore improper cytosolic Ca 2+ 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.

Extra-mitochondrial mouse frataxin and its implications for mouse models of Friedreich’s ataxia

“…Mitochondrial dysfunction resulting from frataxin deficiency is considered to be an underlying cause of the devastating genetic disease of Friedreich's ataxia (FRDA) 10,11 , which is characterized by progressive neurodegeneration and hypertrophic cardiomyopathy 12,13 . In order to conduct mechanistic studies of mitochondrial dysfunction and/or to test potential therapeutic approaches for treating diseases such as FRDA, multiple mouse models of frataxin deficiency have been developed [14][15][16][17][18][19][20][21][22] .…”

Disarrangement of Endoplasmic reticulum-mitochondria communication impairs Ca2+homeostasis in FRDA

“…We have recovered function and structure of MAMs with NAC or Trolox treatment, demonstrating a direct relationship between Ca 2+ dyshomeostasis and oxidative stress. Several authors have described oxidative stress together with Ca 2+ dysregulation in different FRDA models (Abeti et al, 2018b;Chiang et al, 2018;Mollá et al, 2019;Wong et al, 1999). It is interesting to emphasize that lipid peroxidation has been described in FRDA patients (Emond et al, 2000) as well as in flies and different tissues from FRDA mice models (Abeti et al, 2015(Abeti et al, , 2016Al-Mahdawi et al, 2006;Navarro et al, 2010).…”

A new FRDA mouse model [Fxnnull:YG8s(GAA) > 800] with more than 800 GAA repeats

“…These mice exhibit not only moderate decrease in frataxin expression, but also mild progressive behavioral deficits, reduced aconitase activities, GAA repeat instability and some epigenetic modifications. These models have been used as powerful tools to understand in depth FRDA pathogenesis ( Bourn et al, 2012 ; Chan et al, 2013 ; Shan et al, 2013 ; Hayashi et al, 2014 ; Chutake et al, 2015 ; Abeti et al, 2016 ), on potential novel therapeutic strategies, such as gene replacement therapy ( Kemp et al, 2018 ), gene therapy ( Khonsari et al, 2016 ; Ouellet et al, 2017 ), as well as in pre-clinical testing of drug compounds ( Li et al, 2013 ; Sahdeo et al, 2014 ; Abeti et al, 2018 ; Cherif et al, 2018 ; Santoro et al, 2018 ; Mollá et al, 2019 ). However, these FXN YAC transgenic mice show a mild phenotype and none of the currently available models represents all the essential key features observed in human FRDA patients.…”