Rajalaxmi Natarajan, PhD
Dec 1st, 2016
A study1 published in the journal eLife by Dr. Hugo J. Bellen’s team at Baylor College of Medicine and Neurological Research Institute (NRI) at Texas Children’s Hospital (TCH) shows that loss of frataxin protein may cause neurodegeneration by accumulation of excess iron in mice and humans.
Fredreich’s ataxia (FRDA) is a progressive neurodegenerative disorder. Most individuals have an onset of FA between the ages of 5 and 18 years and less than 25% of the diagnosed individuals have adult or late onset. The most common symptoms include loss of coordination, fatigue, vision/hearing impairment, slurred speech, diabetes and cardiomyopathy, although mental capabilities of the patients remain intact.
FA is caused by mutations in Frataxin (FXN) gene. FA is inherited in an autosomal recessive manner, meaning that individuals must have two mutated or abnormal copies of this gene. This happens when both biological parents carry at least one copy of the mutated gene and contribute that defective copy to their offspring.
FXN protein is responsible for the proper assembly of iron-sulfur clusters that are incorporated into many metalloproteins, including mitochondrial proteins. Loss of FXN disrupts the electron transport chain (ETC), a series of mitochondrial oxidative and reductive reactions that produce cellular energy. Impaired ETC results in massive production of chemically unstable reactive oxygen species (ROS) that are toxic to the cells.
Until recently, it was proposed that in FRDA patients, loss of FXN function damaged the neurons due to excessive production of ROS. However, contrary to this hypothesis, it has been observed that loss of FXN leads to only a very modest increase in ROS levels in several animal models, including fruit flies. Consistent with that observation, FA patients undergoing anti-oxidant therapy have shown limited or no improvement in several clinical trials.
In an earlier study, the Bellen team found that while mitochondrial function was perturbed in fruit flies lacking frataxin, there was no significant increase in ROS levels. Instead, they had excessive iron accumulation in neurons which was accompanied with an age-dependent neurodegeneration of eye receptors. Based on results from various experiments they concluded that excess iron led to an upregulation in sphingolipid signaling along with unusual activation of two other proteins, the 3-phosphoinositide dependent protein kinase-1 (Pdk1) and a target of this kinase, myocyte enhancer factor-2 (Mef2), which were least in part the cause of the observed neurodegenerative phenotypes.
In this study, the Bellen team led by graduate student Kuchuan Chen found that deletion of FXN in mice is similarly deleterious and leads to neurobehavioral defects. This study shows for the first time that loss of Fxn can lead to an accumulation of iron within the neuronal cell bodies and extracellular spaces of vertebrate brains. Also, consistent with the previous study, they saw an increase in sphingolipid/PDK1/Mef2 signaling in the neurons of Fxn mutant mice as well as in the cardiocytes of FRDA patients. The upregulation of Mef2 may be at the root of the neuronal death and the cardiomyopathy observed in FRDA patients.
Thus, this study shows that accumulation of iron, not reactive oxygen species, is the most likely primary cause of neurodegeneration and cardiomyopathy, a major cause of lethality, in FRDA patients. This study shows that excess iron causes brain and heart cells to degenerate due to the disruption of a highly conserved spingolipid-Pdk1-Mef2 signaling pathway.
The clinical relevance of this study is that it has unearthed many potential drug targets for FRDA that can be further developed into viable therapies.