Previous research has shown that there are changes in the levels and activity of molecules known as sphingolipids in cells in Friedreich’s ataxia (FA). Since 2022, Ataxia UK has awarded two research grants to Dr Sara Anjomani Virmouni and her team at Brunel, University of London, to investigate some of the processes occurring in cells which are disrupted in Friedreich’s ataxia (FA), and to study whether these processes could be targeted by treatment to protect against cell damage in FA. Results from these projects were recently published in the journal iScience.
What happens in the body in FA?
FA is caused by a change in the FXN gene, which contains the instructions for making the frataxin protein. This leads to reduced production of the frataxin protein in cells. Frataxin plays a key role in mitochondria – the energy-producing parts of cells. Low levels of frataxin cause stress to cells – especially in the highly energy-demanding nerve cells and heart cells – causing cell damage, and eventually leading to the symptoms of FA.
What are sphingolipids, and why are they being studied?
Sphingolipids are a type of molecule found naturally in cells, which are an important component of cell membranes, the protective later surrounding cells. Sphingolipids are needed for processes such as cell growth, blood vessel formation and inflammation. Levels of sphingolipids are regulated by a different type of molecule, called enzymes. The researchers were interested in two well studied sphingolipids, called Cer and S1P. The researchers wanted to know whether levels and activity of Cer and S1P are altered in FA, and if targeting them might lessen or reverse the damage caused by FA.
Which models of FA did the researchers look at?
The team studied three models of FA.
Model 1: skin cells from three-to-five people with FA.
Model 2: skin cells from two of the people with FA were converted back into stem cells (the cells from which all other cells are formed). These stem cells were programmed to make neurons and heart cells (the main cells that are damaged in FA).
Model 3: mouse with FA (to represent how cells behave in the living body)
What were the main findings from the study?
The study showed that levels and activity of the sphingolipids Cer and S1P are disrupted in FA, with too much Cer increasing cell death, and too little S1P decreasing cell survival. To see if they could reverse this in the models of FA, the researchers tried different methods to alter the levels and activity of the two sphingolipids being studied. All three methods improved measures of FA in these models.
Overall, targeting sphingolipid processes can increase frataxin, produce antioxidant effects, reduce mitochondrial dysfunction and lower cellular stress in cell and mouse models of FA. These processes may be a potential target for future FA treatments.
What were the main weaknesses of the study?
The research had some weaknesses. For example, the mouse experiments were short-term; longer-term studies are needed to test whether these approaches can improve FA symptoms and progression.
What future work needs to be done?
Overall, the study has shown positive early findings across three FA models, but larger, longer-term studies including looking at the effects of the treatments on FA symptoms are needed before they can test the treatments in humans.
What do these findings mean for people with FA?
Dr. Anjomani Virmouni reflects,
“This work represents an important step in identifying sphingolipid metabolism as a novel and promising pathway for therapeutic development in FA. We are very grateful for Ataxia UK’s commitment to advancing research and improving outcomes for individuals affected by FA. We look forward to continuing this collaboration and to sharing further progress in the future”.
