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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.


Loss of mitochondrial localization of human FANCG causes defective FANCJ helicase

Fanconi anemia (FA) is a unique DNA damage repair pathway. To date, twenty-two genes have been identified which are associated with the FA pathway. Defect in any of those genes causes genomic instability, and the patients bearing the mutation become susceptible to cancer. In earlier work, the authors have identified that Fanconi anemia protein G (FANCG) protects the mitochondria from oxidative stress. In this report, eight patients having mutation (C.65G>C; p.Arg22Pro) in the N-terminal of FANCG were identified. The mutant protein hFANCGR22P is able to repair the DNA and able to retain the monoubiquitination of FANCD2 in FANCGR22P/FGR22P cell. However, it lost mitochondrial localization and failed to protect mitochondria from oxidative stress. Mitochondrial instability in the FANCGR22P cell causes the transcriptional down-regulation of mitochondrial iron-sulfur cluster biogenesis protein Frataxin (FXN) and resulting iron deficiency of FA protein FANCJ, an iron-sulfur containing helicase involved in DNA repair.

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Extra-mitochondrial mouse frataxin and its implications for mouse models of Friedreich's ataxia

Numerous studies of mitochondrial dysfunction in Friedreich's ataxia have been conducted using mouse models of frataxin deficiency. However, mouse frataxin that is reduced in these models, is assumed to be mature frataxin (78-207) by analogy with human mature frataxin (81-210). Using immunoaffinity purification coupled with liquid chromatography-high resolution tandem mass spectrometry, this study finds that mature frataxin in mouse heart (77%), brain (86%), and liver (47%) is predominantly a 129-amino acid truncated mature frataxin (79-207) in which the N-terminal lysine residue has been lost. Mature mouse frataxin (78-207) only contributes 7-15% to the total frataxin protein present in mouse tissues. The authors have also found that truncated mature frataxin (79-207) is present primarily in the cytosol of mouse liver; whereas, frataxin (78-207) is primarily present in the mitochondria. These findings, which provide support for the role of extra-mitochondrial frataxin in the etiology of Friedreich's ataxia, also have important implications for studies of mitochondrial dysfunction conducted in mouse models of frataxin deficiency.

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A Highly Conserved Iron-Sulfur Cluster Assembly Machinery between Humans and Amoeba Dictyostelium discoideum: The Characterization of Frataxin

This group proposes to use the amoeba Dictyostelium discoideum, as a biological model to study the biosynthesis of Iron-Sulfur Clusters ([Fe-S]) at the molecular, cellular and organism levels. First, they have explored the D. discoideum genome looking for genes corresponding to the subunits that constitute the molecular machinery for Fe-S cluster assembly and, based on the structure of the mammalian supercomplex and amino acid conservation profiles, inferred the full functionality of the amoeba machinery. The recombinant mature form of D. discoideum frataxin protein (DdFXN), the kinetic activator of this pathway, was expressed and characterized. DdFXN is monomeric and compact. The analysis of the secondary structure content, calculated using the far-UV CD spectra, was compatible with the data expected for the FXN fold, and near-UV CD spectra were compatible with the data corresponding to a folded protein. In addition, Tryptophan fluorescence indicated that the emission occurs from an apolar environment. However, the conformation of DdFXN is significantly less stable than that of the human FXN, (4.0 vs. 9.0 kcal mol-1, respectively). Based on a sequence analysis and structural models of DdFXN, this study investigated key residues involved in the interaction of DdFXN with the supercomplex and the effect of point mutations on the energetics of the DdFXN tertiary structure. More than 10 residues involved in Friedreich's Ataxia are conserved between the human and DdFXN forms, and a good correlation between mutational effect on the energetics of both proteins were found, suggesting the existence of similar sequence/function/stability relationships. Finally, this information was integrated in an evolutionary context which highlights particular variation patterns between amoeba and humans that may reflect a functional importance of specific protein positions. Moreover, the complete pathway obtained forms a piece of evidence in favor of the hypothesis of a shared and highly conserved [Fe-S] assembly machinery between Human and D. discoideum.

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Global, multi-stakeholder, consortium launched to study neuroimaging biomarkers for Friedreich Ataxia

A Natural History Study to TRACK Brain and Spinal Cord Changes in Individuals with Friedreich Ataxia (TRACK-FA)

Downingtown, PA (September 24, 2020) - The Friedreich’s Ataxia Research Alliance (FARA) and partner organizations proudly announce an international consortium of academic, industry, and patient advocacy partners to launch a natural history study to TRACK brain and spinal cord changes in individuals with Friedreich’s ataxia (FA). Friedreich’s ataxia is a rare debilitating, life-shortening, degenerative neuro-muscular disorder. About 5,000 people in the United States and 15,000 worldwide live with FA.

The TRACK-FA study is the most extensive worldwide longitudinal, multi-center neuroimaging study in FA with 200 children and adults (and ~100 matched controls) and three assessments (baseline, 12-month, and 24-month follow-up). The TRACK-FA study aims to improve understanding of the natural disease history of FA (specifically, related to changes in the brain and spinal cord), validate neuroimaging measurements in FA to deliver a set of trial-ready biomarkers, and develop a comprehensive database to facilitate ongoing community research and discovery. The study is a collaboration between six international sites, including, Monash University (Australia), University of Minnesota (USA), Aachen University (Germany), University of Campinas (Brazil), University of Florida (USA), and the Children’s Hospital of Philadelphia (USA). FARA (USA) and several industry partners will provide input on study design, endpoints, and monitoring. The goal is to begin enrolling before the end of 2020, as individual sites are able to return to clinical research activities. Updates on opening enrollment will be shared through each of the study sites, FARA and clinicaltrials.gov, clinicaltrials.gov/ct2/show/NCT04349514

FARA CEO, Jennifer Farmer said, “TRACK-FA is a great example of public-private partnership and research advancement in the pre-competitive space. As we all need better tools to understand and measure what is happening in the FA brain and spinal cord, FARA is proud to support this international consortium. The goal of TRACK-FA is to deliver such tools for future clinical trials.”

Professor Georgiou-Karistianis from Monash University states, “We are very excited that this international collaboration brings together significant expertise in FA from across the globe. For the first time, TRACK-FA will validate neuroimaging biomarkers so that they’re ready to be pushed through the drug development pipeline. TRACK-FA provides real promise to accelerate the effort for new treatments in this rare disease.”

The study has been registered with ClinicalTrials.gov, clinicaltrials.gov/ct2/show/NCT04349514 and provides more information about TRACK-FA and a list of sites with contact information.

Emerging therapies in Friedreich's Ataxia

This review covers past and emerging therapies for Friedreich's Ataxia (FRDA), including antioxidants and mitochondrial-related agents, nuclear factor erythroid-derived 2-related factor 2 (Nrf2) activators, deuterated polyunsaturated fatty acids, iron chelators, histone deacetylase (HDAC) inhibitors, trans-activator of transcription (TAT)-frataxin, interferon gamma (IFNγ), erythropoietin, resveratrol, gene therapy, and anti-sense oligonucleotides (ASOs), among others. While drug discovery has been challenging, new and exciting prospective treatments for FRDA are currently on the horizon, including pharmaceutical agents and gene therapy. Agents that enhance mitochondrial function, such as Nrf2 activators, dPUFAs and catalytic antioxidants, as well as novel methods of frataxin augmentation and genetic modulation will hopefully provide treatment for this devastating disease.

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