Abstract
Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by mutations in Frataxin (FXN). Loss of FXN causes impaired mitochondrial function and iron homeostasis. An elevated production of reactive oxygen species (ROS) was previously proposed to contribute to the pathogenesis of FRDA. We recently showed that loss of frataxin homolog (fh), a Drosophila homolog of FXN, causes a ROS independent neurodegeneration in flies (Chen et al., 2016). In fh mutants, iron accumulation in the nervous system enhances the synthesis of sphingolipids, which in turn activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2) to trigger neurodegeneration of adult photoreceptors. Here, we show that loss of Fxn in the nervous system in mice also activates an iron/sphingolipid/PDK1/Mef2 pathway, indicating that the mechanism is evolutionarily conserved. Furthermore, sphingolipid levels and PDK1 activity are also increased in hearts of FRDA patients, suggesting that a similar pathway is affected in FRDA.
Highlights
Friedreich’s ataxia (FRDA) is the most prevalent form of recessive cerebellar ataxia characterized by neurodegeneration and cardiomyopathy
To test if the iron/sphingolipid/PDK1/myocyte enhancer factor-2 (Mef2) pathway is activated in vertebrates in vivo upon loss of Fxn, we reduced Fxn levels in the mouse nervous system by using the associated virus (AAV) and CRISPR/Cas9 system (Swiech et al, 2014)
We show that removal of Fxn in the central nervous system using AAV and CRISPR/Cas9 causes behavioral and neurological phenotypes in mice
Summary
FRDA is the most prevalent form of recessive cerebellar ataxia characterized by neurodegeneration and cardiomyopathy. Loss of FXN has been shown to cause mitochondrial dysfunction in several model organisms (Anderson et al, 2005; Puccio et al, 2001; Rotig et al, 1997). Whether iron accumulates in the nervous system is still under debate, as it has been reported that iron levels are not altered in the nervous system of a conditional knockout mouse model and in FRDA patients (Puccio et al, 2001; Simon et al, 2004; Solbach et al, 2014). In FRDA patients, iron was shown to accumulate in the dentate nuclei or in glia cells of dorsal root ganglia (Boddaert et al, 2007; Koeppen et al, 2009). The iron deposition phenotype is still controversial in mouse models and FRDA patients, and the role of iron in the pathophysiology of FRDA has not yet been determined
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