Friedrich’s ataxia (FRDA) is a recessive hereditary ataxia, caused by a specific genetic mutation that alters frataxin protein production. This results in progressive neurodegeneration affecting speech, movement, retinal and cardiac function, and is ultimately fatal after decades of worsening symptoms.
Despite the neurodegenerative nature of the disease, cognitive function is not affected and the primary cause of death for FRDA patients is heart failure. At present there are no therapies available to FRDA patients, highlighting the need to identify effective targets for therapeutics, as well as discovering and trialling potential therapeutic regimes.
A research group from Philadelphia, USA, have investigated the role of apolipoprotein A-I in the development of cardiomyopathy and heart failure in FRDA. The researchers established that FRDA patients have reduced levels of apolipoprotein A-I (ApoA-I) in their serum, a protein which is associated with heart attack and cardiomyopathy when in low levels.
[caption id=“attachment_94570” align=“alignright” width=“320”] Apolipoprotein A1[/caption]
In fact, the differences in ApoA-I levels recorded for FRDA patients and the control group are very similar to those found in tobacco smokers and non-smokers.
Tobacco smoking, of course, has been shown to contribute to cardiovascular disease and significantly increase the risk of heart failure. This exemplifies the potential therapeutic advantages of altering ApoA-I levels in FRDA patients, reducing the risk of heart failure and extending the lifespan of patients.
Reductions in high density lipoprotein (HDL) and ApoA-I levels are associated with an increased risk of heart failure in the general population, but in previous FRDA cohort studies the effects of HDL and ApoA-I have been inconsistent.
Some studies have shown that reduced levels of both in FRDA patients promote heart failure, but others show inconclusive correlations. The authors address this in their publication, stating that the techniques used may have suffered from cross reactivity, which compared to the highly sensitive mass spectrometry technique used in this study may hold true.
Additionally, the researchers used a cell line with its ability to produce frataxin removed – like what happens in FRDA cells – to investigate assess levels of ApoA-I and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), a protein associated which upregulates ApoA-I production.
They found that cells without frataxin produced much lower levels of ApoA-I compared to controls, but this effect was rescued by treatment with simvastatin – a commonly prescribed statin for cardiovascular diseases and to reduce cholesterol levels.
HMG-CoA is normally converted into mevalonic acid (MVA) through a HMG-CoA reductase enzyme catalyst; statins directly inhibit HMG-CoA reductase, producing an increased level of HMG-CoA.
In previous experiments MVA has been shown to eliminate the production of ApoA-I, therefore the use of statins has the potential to increase levels of Apo-A-I and reduce the risk of adverse cardiovascular events in FRDA patients.
[caption id=“attachment_94569” align=“aligncenter” width=“680”] ApoA-I and HMG-CoA levels in HepG2 cells after treatment with simvastatin.
(A) Relative levels of secreted ApoA1.
(B) Relative HMG-CoA levels. Levels (means ± SD; n = 3) were normalized to cellular protein.
P values are differences between simvastatin treated group and 0.1% DMSO treated group for each siRNA. *P < 0.05, **P < 0.01, ***P < 0.001. Cells were treated with simvastatin (SIM) was for 48 h.
Credit: Wang Q, et al. CC-BY[/caption]
Interestingly the group found that four of the FRDA patients tested (out of 95), had normal levels of ApoA-I in their serum. This suggests that these patients may not have a higher risk of cardiovascular disease and heart failure.
Overall, the evidence from this research suggests that Friedrich’s Ataxia patients would benefit from statin treatments to increase ApoA-I levels. Currently FRDA patients are prescribed different medications to combat cardiovascular issue, with statins only recently being investigated for this purpose. The research from this paper highlights statins as a potential solution to this issue.
Statins are widely used for a variety of disorders – so the toxicology of the drugs are reasonably well known – and could potentially alleviate the cardiovascular burden attributed to FRDA patients.
QingQing Wang, Lili Guo, Cassandra J. Strawser, Lauren A. Hauser, Wei-Ting Hwang, Nathaniel W. Snyder, David R. Lynch, Clementina Mesaros, Ian A. Blair Low apolipoprotein A-I levels in Friedreich’s ataxia and in frataxin-deficient cells: Implications for therapy PLOS One: February 15, 2018. https://doi.org/10.1371/journal.pone.0192779
Author: Geoffrey Potjewyd; Regenerative Medicine & Neuroscience PhD student at the University of Manchester. Top Image: QingQing Wang, et al. CC-BY. Schematic showing changes in glycolysis, lipid metabolism, and fatty acid biosynthesis/oxidation, and ApoA-I expression in FA.