Abnormally low levels of the protein HAX-1 correlate with decreased amounts of frataxin in cells from people with Friedreich’s ataxia (FA), suggesting this protein could be used as a biomarker in the disease.
The study with that finding, “Frataxin deficiency in Friedreich’s ataxia is associated with reduced levels of HAX-1, a regulator of cardiomyocyte death and survival,” was published in Human Molecular Genetics.
FA is caused by decreased levels of the protein frataxin, typically as a consequence of a GAA trinucleotide repeat. This has myriad effects on cells, most notably cells in the pancreas, brain, and heart.
In this study, researchers first took a blood cell line derived from a person with FA, and experimentally induced the expression of frataxin in the cells. Then they compared the gene expression profiles of the cells with or without the frataxin induction, essentially looking to see what genes were “on” in the presence of frataxin but “off” in its absence, or vice versa.
The gene affected most significantly was HAX-1 (HS-1-associated protein X-1), which provides instructions for making a protein of the same name. This protein plays numerous roles throughout the body. Among them, “HAX-1 is highly expressed in the heart where it plays a role in cardioprotection,” the researchers wrote.
The researchers then validated this finding in a human kidney cell line (HEK293). When frataxin levels were increased in these cells there was a corresponding increase in HAX-1 levels, and when frataxin levels decreased, so did HAX-1 levels.
These same findings also were observed in a human heart cell line (AC16). Interestingly, in these cells, changes in frataxin levels also resulted in corresponding changes in the levels of two antioxidant proteins, Nrf2 and MnSOD.
Based on this and the known heart-protecting functions of HAX-1, the researchers predicted that HAX-1 might help these heart cells cope with oxidative stress. Indeed, increasing HAX-1 levels — even in cells lacking frataxin — made them more resistant to oxidative stress. That is, when the cells were treated with an oxidative agent (hydrogen peroxide), more of them survived when HAX-1 levels were increased.
The researchers then assessed levels of frataxin and HAX-1 in cell lines derived from 11 people with FA. On average, HAX-1 levels (both protein and mRNA) were reduced in these cells compared to cell lines derived from people without FA. It should be stressed that this difference was an average based on the groups as a whole; some individuals with FA did have higher HAX-1 levels than some without.
The researchers measured frataxin and HAX-1 levels in blood cells taken directly from people with or without FA (as opposed to cell lines derived from them). For mRNA expression, 39 people with FA (average age 42) and 23 people without (average age 41) were analyzed. For protein expression, 41 people with FA (average age 39) and 27 people without (average age 41) were analyzed.
As in the cell lines, frataxin and HAX-1 levels were correlated with each other at both mRNA and protein levels. Additionally, levels of Nrf2 were correlated with both HAX-1 and frataxin levels in these cells (though there were no significant differences in Nrf2 levels between people with or without FA).
No significant differences were found in frataxin or HAX-1 levels in comparisons of people with FA who did or did not have hypertrophic cardiomyopathy, a heart condition in which the walls of the heart become abnormally thick.
Overall, these data support the idea that HAX-1 is dysregulated in FA as a result of the lack of frataxin. This implies that HAX-1 might be associated with clinical features of disease, making it a possible biomarker. It even could be a therapeutic target for heart disease, but more research will be needed to validate these ideas.
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