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Scientific News

FARA funds research progress

In this section, you will find the most recent FA research publications, many of which are funded by FARA, as well as information on upcoming conferences and symposiums. You can search for articles by date using the archive box in the right hand column. To locate FARA Funded or Supported Research, click the hyperlink in the right hand column. You may also search for specific content using key words or phrases in the search button at the top right of your screen. Please be sure to visit other key research sections of our website for information on FARA’s Grant Program and the Treatment Pipeline.



Structural and functional characterization of a frataxin from a thermophilic organism

Frataxins form an interesting family of iron-binding proteins with an almost unique fold and are highly conserved from bacteria to primates. They have a pivotal role in iron-sulfur cluster biogenesis as regulators of the rates of cluster formation, as it is testified by the fact that frataxin absence is incompatible with life and reduced levels of the protein lead to the recessive neurodegenerative disease Friedreich's ataxia. Despite its importance, the structure of frataxin has been solved only from relatively few species. Here, this group discusses the X-ray structure of frataxin from the thermophilic fungus Chaetomium thermophilum, and the characterization of its interactions and dynamics in solution. They show that this eukaryotic frataxin has an unusual variation of the classical frataxin fold: the last helix is shorter than in other frataxins which results in a less symmetrical and compact structure. The stability of this protein is comparable to that of human frataxin, currently the most stable amongst the frataxin orthologues. They also characterized the iron-binding mode of C. thermophilum frataxin and demonstrated that it binds it through a semi-conserved negatively charged ridge on the first helix and beta-strand. Moreover, this frataxin is also able to bind the bacterial ortholog of the desulfurase, which is central in iron-sulfur cluster synthesis, and act as its inhibitor.

Read the entire article HERE

Longitudinal evaluation of iron concentration and atrophy in the dentate nuclei in friedreich ataxia

In FA patients, the dentate nuclei of the cerebellum are known to degenerate, but there is little understanding of how they change over the course of the disease. This group used in vivo magnetic resonance imaging, including quantitative susceptibility mapping, to investigate changes in iron concentration and volume in the dentate nuclei in individuals with Friedreich ataxia (n = 20) and healthy controls (n = 18) over a 2-year period. They found that the longitudinal rate of iron concentration was significantly elevated bilaterally in participants with Friedreich ataxia relative to healthy controls. Atrophy rates did not differ significantly between groups. Change in iron concentration and atrophy both correlated with baseline disease severity or duration, indicating sensitivity of these measures to disease stage. Specifically, atrophy was maximal in individuals early in the disease course, whereas the rate of iron concentration increased with disease progression. Progressive dentate nucleus abnormalities are evident in vivo in Friedreich ataxia, and the rates of change of iron concentration and atrophy in these structures are sensitive to the disease stage. The findings are consistent with an increased rate of iron concentration and atrophy early in the disease, followed by iron accumulation and stable volume in later stages. This pattern suggests that iron dysregulation persists after loss of the vulnerable neurons in the dentate. The significant changes observed over a 2-year period highlight the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool.

Read the entire article HERE

Drug repositioning screening identifies etravirine as a potential therapeutic for friedreich's ataxia

Given that levels of residual frataxin critically affect disease severity, the main goal of a specific therapy for Friedreich's ataxia is to increase frataxin levels. With the aim to accelerate the development of a new therapy for Friedreich's ataxia, this group took a drug repositioning approach to identify market-available drugs able to increase frataxin levels. Using a cell-based reporter assay to monitor variation in frataxin amount, they performed high-throughput screening of a library containing 853 U.S. Food and Drug Administration-approved drugs. Among the potentially interesting candidates isolated from the screening, they focused their attention on etravirine, an antiviral drug currently in use as an anti-human immunodeficiency virus therapy. In this paper, they show that etravirine can promote a significant increase in frataxin levels in cells derived from Friedreich's ataxia patients, by enhancing frataxin messenger RNA translation. Importantly, frataxin accumulation in treated patient cell lines is comparable to frataxin levels in unaffected carrier cells, suggesting that etravirine could be therapeutically relevant. Indeed, etravirine treatment restores the activity of the iron-sulphur cluster containing enzyme aconitase and confers resistance to oxidative stress in cells derived from Friedreich's ataxia patients. Considering its safety profile along with its ability to increase frataxin levels and correct some of the disease-related defects, etravirine represents a promising candidate as a therapeutic for Friedreich's ataxia.

Read the entire article HERE

Differences in the determinants of right ventricular and regional left ventricular long-axis dysfunction in Friedreich ataxia

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative condition which also has effects on the heart. In 96% of affected individuals FRDA is due to homozygosity of a GAA repeat expansion in intron 1 of the frataxin (FXN) gene. The number of GAA repeats have been shown to relate to disease severity in FRDA, this thought to be via an inverse relationship of GAA repeat number and cellular frataxin levels. This group investigated the effects of FRDA on regional long axis function of the left and right ventricles, and also the relationship of long axis systolic (s`) and early diastolic (e`) peak velocities with GAA repeat number on the shorter (GAA1) and longer FXN alleles (GAA2). The study group of 78 adult subjects (age 32±9 years) with FRDA and normal left ventricular (LV) ejection fraction were compared to 54 healthy control subjects of similar age, sex and body size. Tissue Doppler imagin g (TDI) signals were recorded at the mitral annulus for measurement of s` and e`of the septal, lateral, anterior and inferior walls and at the tricuspid annulus for measurement of right ventricular (RV) s` and e`. All the regional LV s` and e`, and both RV s` and RV e`, were lower in individuals with FRDA compared to controls (p<0.001 for all). On multivariate analysis, which included LV septal wall thickness (SWT), RV s` and RV e` were both inversely correlated with GAA1 (β = -0.32 & -0.33, respectively, p = 0.01), but not with GAA2, whereas anterior and lateral s` were both inversely correlated with GAA2 (β = -0.25 and β = -0.28, p = 0.02) but not with GAA1. Increasing SWT was the most consistent LV structural correlate of lower s` and e`, whereas age was a consistent inverse correlate of e` but not of s`.There are generalized abnormalities of both LV regional and RV long axis function in FRDA, but there are also regional differences in the association of this dysfunction with the smaller and larger GAA repeats in the FXN gene.

Read the entire article HERE

GRP75 overexpression rescues frataxin deficiency and mitochondrial phenotypes in Friedreich Ataxia cellular models

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein crucial for iron-sulphur cluster biogenesis and ATP production. Currently there is no therapy to slow down the progression of FRDA. Recent evidence indicates that posttranslational regulation of residual frataxin levels can rescue some of the functional deficit of FRDA, raising the possibility of enhancing levels of residual frataxin as a treatment for FRDA. Here, we present evidence that mitochondrial molecular chaperone GRP75, also known as mortalin/mthsp70/PBP74, directly interacts with frataxin both in vivo in mouse cortex and in vitro in cortical neurons. Overexpressing GRP75 increases the levels of both wild-type frataxin and clinically relevant missense frataxin variants in HEK293 cells while clinical GRP75 variants such as R126W, A476T and P509S impair the binding of GRP75 with frataxin and the effect of GRP75 on frataxin levels. In addition, GRP75 overexpression rescues frataxin deficiency and abnormal cellular phenotypes such as the abnormal mitochondrial network and decreased ATP levels in FRDA patient-derived cells. The effect of GRP75 on frataxin might be in part mediated by the physical interaction between GRP75 and mitochondrial processing peptidase (MPP), which makes frataxin more accessible to MPP. As GRP75 levels are decreased in multiple cell types of FRDA patients, restoring GRP75 might be effective in treating both typical FRDA patients with two GAA repeat expansions and compound heterozygous patients with point mutations.

Read the entire article HERE

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