Limiting iron absorption in gut may help extend lifespan in Friedreich’s ataxia
Study: Too little frataxin leaves brain's glial cells vulnerable to iron overload
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Too little of the protein frataxin makes glial cells, which protect and nourish neurons, especially vulnerable to iron overload, while limiting how much iron is absorbed in the intestine may help extend survival and ease symptoms in Friedreich’s ataxia, according to a study that used flies to model the disease.
“While these findings do not directly support dietary iron limitation as a therapeutic recommendation for patients, they highlight systemic [whole-body] iron flux as a potential contributor to [Friedreich’s ataxia],” researchers wrote in the study “Limiting intestinal iron absorption rescues glial defects and extends lifespan in a Drosophila model of Friedreich’s ataxia,” which was published in Neurobiology of Disease.
Iron accumulated in brains of frataxin-deficient flies
Friedreich’s ataxia is chiefly caused by an abnormal expansion of a DNA sequence called a GAA repeat in the FXN gene, which reduces the production of frataxin. This protein helps cell structures called mitochondria produce energy by building iron-sulfur clusters. Without enough frataxin, mitochondria are overloaded with iron. However, it is unclear whether excess iron contributes to how the disease progresses.
In a study in France, the researchers used flies carrying the same type of GAA expansion found in patients diagnosed with Friedreich’s ataxia. These flies produce less frataxin and have a very short lifespan. Male flies normally live for fewer than 10 days on average, compared with about 40 days for healthy flies.
The researchers first looked at genes that control how iron moves and is stored in the body. Although the activity of several of these genes was lower in the frataxin-deficient flies, the changes were relatively small. The total amount of iron in the larvae was also not significantly different from that in healthy flies.
However, in frataxin-deficient flies, iron accumulated in the brain and in the ventral nerve cord, which is part of the central nervous system. Some accumulation was also found in cells around the heart, but little or no detectable accumulation was found in the intestine or developing tissues. This suggests that too little frataxin is associated with iron accumulation in particular tissues rather than throughout the entire body.
BPS increased survival in developing flies
The researchers then asked whether reducing available iron could extend survival. They tested several iron chelators, which are substances that bind iron and make it less available for chemical reactions. One iron chelator, deferoxamine, increased lifespan by a mean of 23%, while bathophenanthroline disulfonic acid (BPS) increased lifespan by a mean of 93%.
BPS mainly reduces how much iron is absorbed in the intestine. Giving it while the flies were developing increased survival, whereas starting treatment during adulthood did not. A higher dose was also less effective than a low dose, showing that more of a treatment is not necessarily better. BPS did not increase production of the frataxin protein.
The researchers confirmed this idea using a second approach. They reduced Malvolio — a protein that helps move iron —in the intestine to prevent less iron from being absorbed from food. This nearly doubled the lifespan of the frataxin-deficient flies. Together, the findings suggest that limiting how much iron is absorbed in the intestine may help counteract the effects of too little frataxin.
Our findings identify glial cells as early and preferential targets of frataxin deficiency in an iron-dependent manner and support the … relevance of intestinal iron uptake as a potential modulator of disease severity.
Interestingly, frataxin-deficient flies were extremely sensitive to dietary iron. When iron was added to their food, very few developed into adults. BPS partially protected them from excess iron. It also reduced the amount of iron detected in the central nervous system, although it did not completely return it to normal levels.
The frataxin-deficient flies had poor spontaneous movement, meaning they were less active during normal daily behavior. BPS increased their overall activity by about 76% and improved the normal morning and evening activity peaks. However, BPS did not correct enlargement of the heart chambers.
When looking at the nervous system in greater detail, the researchers found that the brains and ventral nerve cords of frataxin-deficient larvae were smaller than those of healthy flies. The glial cells showed abnormal shapes and their proportion compared with neurons was reduced, suggesting that glial cells may be most vulnerable to low frataxin when excess iron is present. BPS prevented these changes.
Too little frataxin appears to make the nervous system, particularly glial cells, unusually sensitive to iron. Limiting the absorption of iron from food extended survival and improved movement.
“Our findings identify glial cells as early and preferential targets of frataxin deficiency in an iron-dependent manner and support the … relevance of intestinal iron uptake as a potential modulator of disease severity,” the researchers wrote.
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