Scientific News

Friedreich ataxia is caused by an expanded (GAA*TTC)n sequence, which is unstable during intergenerational transmission and in most patient tissues, where it frequently undergoes large deletions. We investigated the effect of DSB repair on instability of the (GAA*TTC)n sequence. Linear plasmids were transformed into Escherichia coli so that each colony represented an individual DSB repair event. Repair of a DSB within the repeat resulted in a dramatic increase in deletions compared with circular templates, but DSB repair outside the repeat tract did not affect instability. Repair-mediated deletions were independent of the orientation and length of the repeat, the location of the break within the repeat or the RecA status of the strain. Repair at the center of the repeat resulted in deletion of approximately half of the repeat tract, and repair at an off-center location produced deletions that were equivalent in length to the shorter of the two repeats flanking the DSB.

Read More: Repair of DNA double-strand breaks...

PURPOSE:
Friedreich ataxia (FRDA) is characterized by GAA expansions in the intron 1 of the frataxin gene correlating with disease onset and progression as well as cardiac affection. Accordingly, FRDA patients with early disease onset show a clear impairment of mitochondrial function in the myocardium. The purpose of this study was to investigate cardiac function and high-energy phosphate metabolism in FRDA patients with late disease onset.

PROCEDURES:
Using a 1.5 T magnetic resonance scanner, cardiac phosphorus-31 two-dimensional chemical shift imaging was performed in ten patients (seven male, three female) with a late onset of FRDA and in 35 healthy, male controls. Ejection faction (EF) and interventricular septum thickness (IST) were determined by echocardiography.

Read More: Phosphorus-31 two-dimensional chemical shift imaging in the myocardium of patients with late onset of Friedreich ataxia

In Friedreich's ataxia, reduction of the mitochondria protein frataxin results in the accumulation of iron and reactive oxygen species, which leads to oxidative damage, neurodegeneration and a diminished lifespan. Recent studies propose that frataxin might play a role in the antioxidative process. Here we show that overexpression of Drosophila frataxin in the mitochondria of female transgenic animals increases antioxidant capability, resistance to oxidative stress insults, and longevity. This suggests that Drosophila frataxin may function to protect the mitochondria from oxidative stresses and the ensuing cellular damage.

Read More: Overexpression of frataxin in the mitochondria increases resistance to oxidative stress and extends lifespan in Drosophila

The inherited ataxias are a large, heterogeneous group of neurodegenerative disorders caused by a variety of gene mutations, the effects of which are exerted through different pathogenic mechanisms. Despite this diversity, oxidative stress seems to be a common factor in the pathogenesis of these disorders, indicating that antioxidants might be potential therapeutics for these currently incurable conditions. Some inherited ataxias, such as ataxia with vitamin E deficiency, are directly caused by defects in small-molecule antioxidants and might be treated by supplying the defective molecule. In most ataxias, however, oxidative stress has more-complex disease-specific causes and consequences, which must be better understood to enable effective treatments to be developed. Results from studies in cellular and animal models need to be brought to the clinic through rigorous trials. The rarity of each of these diseases can, however, make trial design and execution a very difficult task.

Read More: Drug Insight: antioxidant therapy in inherited ataxias