Endoplasmic Reticulum Stress Could Be Treatment Target for Friedreich’s Ataxia, Study Suggests
Endoplasmic reticulum stress due to loss of frataxin protein plays a major role in the development of Friedreich’s ataxia and could be targeted for therapy, a study involving fruit flies shows.
The study, “Mitofusin-Dependent ER Stress Triggers Glial Dysfunction and Nervous System Degeneration in a Drosophila Model of Friedreich’s Ataxia,” was published in the journal Frontiers in Molecular Neuroscience.
Friedreich’s ataxia (FA) develops due to a deficiency of the protein frataxin, which resides in the mitochondria — which supply power to cells — and is known to play a role in mitochondrial energy production.
Mitochondria and the endoplasmic reticulum (ER) form structural and functional networks necessary to maintain cellular homeostasis (balance) and play important roles in cell death and survival.
One of the ways the cell’s equilibrium can be thrown off is through the accumulation of unfolded proteins in the ER, which causes cells to adapt and acquire a stress condition called ER stress. A loss of frataxin has been shown to increase ER stress, but nobody has discovered a direct mechanism linking ER stress with FA yet.
In recent years, several studies have shown that mitochondrial homeostasis is conserved in fruit flies and can serve as an excellent model to analyze problems with mitochondria function.
Based on this, researchers conducted a screen to identify which genes controlled mitochondrial homeostasis in a fruit fly model of FA.
They discovered that when glial cells — a type of neuron — were depleted of mitofusin (Marf), it reversed FA. Marf in fruit flies is known to play crucial roles in mitochondrial dynamics such as fusion, degradation, and the interface between mitochondria and ER.
Next, researchers analyzed the effects of frataxin depletion on the processes in which Marf is involved, including mitochondrial structure, mitophagy (degradation of mitochondria), and ER function in the fly FA model.
Results indicated that loss of frataxin had a small impact on mitochondrial structure but maintained mitophagy. More significantly, frataxin loss led to a significant increase in ER stress response, indicating a major novel mechanism through which loss of frataxin causes damage.
This led researchers to wonder whether reducing ER stress activity was enough to improve FA. Using two different chemical compounds, researchers did, in fact, show that reducing ER stress improved the effects of frataxin deficiency in three different fly FA models.
Results from this study suggests that ER stress is a novel and crucial player in the progression and cause of FA.
The authors explain that these findings, “define a new pathological [disease] mechanism in FRDA [Friedreich’s ataxia], linking mitochondrial dysfunction due to frataxin deficiency and mitofusin-mediated ER stress, which might be responsible for characteristic cellular features of the disease and also suggests ER stress as a therapeutic target.”