Friedreich’s ataxia is a genetic a neurodegenerative disease that leaves its victims with difficulty walking, a loss of sensation in the arms and legs and impaired speech caused by degeneration of nerve tissue in the spinal cord. The disease is caused by the presence of an expanded repetition of a three letter genetic sequence, GAA in the FXN gene, which encodes for frataxin, a protein required for proper function of mitochondria (the cell’s “powerplants) that generate the fuel to keep all other cell functions running. One in 40,000 individuals has this condition. Healthy people usually have 8 to 34 GAA repeats, carriers have 35 to 70 repeats, and individuals that exhibit disease symptoms have more than 70 — and commonly have hundreds of repeats. With more DNA repeats, it becomes increasingly difficult for the cells to “read” the FXN gene and produce a properly working version of the protein. It is known that in patients’ tissues, the GAA repeats are unstable and continuously expand and contract.
Understanding the mechanism of GAA repeat expansion and contraction (especially the latter) is important to developing this strategy for battling the currently incurable disease. Numerous theories have been advanced as to how the DNA repeats contract, although the precise details of the mechanism remained largely unknown. Scientists at Tufts University have identified a molecular mechanism that could reverse the genetic defect responsible for Friedreich’s ataxia. The researchers reported in the Proceedings of the National Academy of Sciences that the genetic anomaly that causes the disease — the multiple repetition of a three letter DNA sequence — could potentially be reversed by enhancing a natural process that contracts the repetitive sequences in living tissue. In order to pinpoint the actual mechanism, the authors of the study developed an experimental system in yeast to quantitatively measure the effects of different interventions on contractions of DNA repeats,
They found that contractions happened usually during the process of DNA replication, in the course of what is referred to as “lagging strand synthesis.” When the two strands of DNA are copied, one strand is replicated in a continuous manner, while the other must be assembled from smaller pieces stitched together. This is the lagging strand, so named because its more complex synthesis limits the rate at which the DNA can be copied. The normal structure of DNA is a double helix consisting of two strands winding around each other. A triple helix, in contrast, consists of three strands wrapped in a helical twist. As the replication machinery moves across the lagging strand, it cannot easily bypass a triplex formed by the repeat. When the replication machinery jumps over this triple helix hurdle, the copied DNA strand ends up with fewer GAA repeats. The Tufts researchers found that the contraction of repeats depends on the ability of the DNA repeat to form an unusual triple-helical DNA structure along the laggin strand.
The DNA repeats literally gum up the works. They can also cause other mutations in the surrounding DNA, or make chromosomes extremely fragile, breaking into pieces, or rearranging themselves. Though no effective therapy is not available, novelties are up. Another team from examined the metabolic, neuroprotective and frataxin-inducing effects of glucagon-like-peptide 1 (GLP-1) analogs in in vivo and in vitro models and in Friedreich ataxia patients. The GLP-1 analog exenatide currently used in diabetes management, improved glucose homeostasis of frataxin-deficient mice through enhanced insulin content and secretion in pancreatic β-cells. Exenatide induced frataxin and iron-sulfur cluster-containing proteins in β-cells and brain, and was protective to sensory neurons in dorsal root ganglia. GLP-1 analogs also induced frataxin expression, reduced oxidative stress and improved mitochondrial function in Friedreich ataxia patients’ induced pluripotent stem cell-derived β-cells and sensory neurons.
The frataxin-inducing effect of exenatide was confirmed in a pilot trial in Friedreich ataxia patients, showing modest frataxin induction in platelets over a 5-week treatment course. Other clinical data exist with other potential neuroprotective agents. Coenzime Q and its derivative idebenone have been found effective at high doses (400-600mg/die) but no at low doses (40-100mg/die). Another potent antioxidant, indole-3-propionic acid has been evaluated in adults with FRDA in a Phase I, multidose, multicenter trial. Acetyl-carnitine at 1gr/twice a day was effective in enhancing muscular tone and overall coordination in a double-blind placebo-controlled clinical trial. Growth factors like erythropoietin (EPO) and insulin-like growth factor (IGF-1) have been tested as well, but in a very small coort and thus the results need confirmation. Finally, epigenetic inducers (histone decaetylase modulators) have been tested; one the most effective seems pimelic-2-aminobenzamide.
Even high doses (3-5g/day of vitamin B3 (nicotinamide), which regulated multiple aspects of nucleic acid metabolism and shows HDAC-like-properties, have been reported effective. So hope is kindled with the expansion of knowledge about the mechanisms of this disease.
- Edited by Dr. Gianfrancesco Cormaci, PhD; specialist in Clinical Biochemistry.
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