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FARA Funded Research

Your generous support has funded all the research listed below.


For more information on FARA-funded research & scientists, please visit FARA Supported Research, Active Clinical Trials and the Featured Scientist.

Expanded GAA repeats impede transcription elongation through the FXN gene and induce transcriptional silencing that is restricted to the FXN locus

This publication includes a description and characterization of 18 fibroblast lines derived from FA patients with diverse GAA repeat lengths. This is the largest collection of these cell lines. Researchers can contact the study authors or FARA if they are interested in learning more accessing these cell lines. In addition, this comprehensive analysis revealed that the GAA-induced silencing effect does not influence expression of neighboring genes upstream or downstream of FXN. Furthermore, no long-range silencing effects were detected across a large portion of chromosome 9. Additionally, results of chromatin immunoprecipitation studies confirmed that histone modifications associated with repressed transcription are confined to the FXN locus. Finally, deep sequencing of FXN pre-mRNA molecules revealed a pronounced defect in the transcription elongation rate in FRDA cells when compared to controls. These results indicate that approaches aimed to reactivate frataxin expression should simultaneously address deficits in transcription initiation and elongation at the FXN locus.

Read more: Expanded GAA repeats impede transcription elongation through the FXN gene and induce transcriptional silencing that is restricted to the FXN locus

Frataxin levels in peripheral tissue in Friedreich ataxia

Have you ever given a blood sample or cheek swab sample for research? This study shares results of frataxin protein measures from more than >500 individuals with FA, including some specific results on frataxin levels in in individuals who have point mutations. This study finds that there was no evidence for change in frataxin levels over time with repeated measures analysis, although linear regression analysis of cross-sectional data predicted a small increase over decades. GAA repeat length predicted frataxin levels in both tissues, and frataxin levels themselves predicted neurological ratings (accounting for age). Compound heterozygous patients for a GAA expansion and a point mutation in FXN generally had lower levels of frataxin than those homozygous for the presence of two GAA repeat expansions, though levels varied dramatically between tissues in some compound heterozygotes for point mutations. The G130V mutation led to decreased levels of frataxin in vitro as well as in vivo, while the R165C mutation produced normal immunoreactive levels of frataxin both in vitro and in vivo. Start codon mutations led to low levels of frataxin in buccal cells but preserved immunoreactive frataxin levels in blood.

Read more: Frataxin levels in peripheral tissue in Friedreich ataxia

Stable isotopes and LC-MS for monitoring metabolic disturbances in Friedreich's ataxia platelets

An LC-MS-based method was used to determine whether platelets isolated from patients with FRDA exhibit differentiable metabolism compared with healthy controls. Isotopologue analysis showed a marked decrease in glucose incorporation with a concomitant increase in palmitate-derived acyl-CoA thioesters in FRDA platelets compared with controls. These findings demonstrate that platelets can be used as a surrogate tissue for in vivo biomarker studies to monitor new therapeutic approaches for the treatment of FRDA.

Read more: Stable isotopes and LC-MS for monitoring metabolic disturbances in Friedreich's ataxia platelets

Phenotypic Screening for Friedreich Ataxia Using Random shRNA Selection

A random, short-hairpin-RNA (shRNA)-expressing library was screened in primary FRDA fibroblasts and identified two shRNAs that reverse the growth/viability defect in an in vitro model of FA. One of these two clones increases frataxin expression in primary FRDA fibroblasts, either as a vector-expressed shRNA or as a transfected short-interfering RNA (siRNA).

Read More: Phenotypic Screening for Friedreich Ataxia Using Random shRNA Selection

Targeting lipid peroxidation and mitochondrial imbalance in Friedreich's ataxia

Pharmacol Res. 2015 Jul 2. pii: S1043-6618(15)00113-9. doi: 10.1016/j.phrs.2015.05.015. [Epub ahead of print] Abeti R, Uzun E, Renganathan I, Honda T, Pook MA, Giunti P
 

Fibroblasts from two FRDA mouse models, YG8R and KIKO, were used to analyse two different categories of protective compounds: deuterised poly-unsaturated fatty acids (dPUFAs) and Nrf2-inducers. The former have been shown to protect the cell from damage induced by lipid peroxidation and the latter trigger the well-known Nrf2 antioxidant pathway. Our results show that the sensitivity to oxidative stress of YG8R and KIKO mouse fibroblasts, resulting in cell death and lipid peroxidation, can be prevented by d4-PUFA and Nrf2-inducers (SFN and TBE-31).

Read More:  Targeting lipid peroxidation and mitochondrial imbalance in Friedreich's ataxia

 

 

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