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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.


 

 

Primary Cultures of Pure Embryonic Dorsal Root Ganglia Sensory Neurons as a New Cellular Model for Friedreich's Ataxia

Primary neuronal cultures represent an essential tool in the study of events related to peripheral neuropathies as they allow to isolate the affected cell types, often originating in complex tissues in which they account for only a few percentage of cells. Neuronal cultures also provide a powerful system to identifying or testing compounds with potential therapeutic effect in the treatment of those diseases. Proprioceptive neurons of the dorsal root ganglia (DRG) are the primary affected cells in Friedreich's Ataxia. This paper describes a model of primary cultures of DRG sensory neurons in which there is an induced the loss of the frataxin protein. THis model can alleviate the issues related to the complexity of DRG tissues and low amount of sensory neuron material in adult mouse. The authors provide a protocol of detailed and optimized methods to obtain high yield of healthy mouse DRG sensory neuron in culture.

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Changes detected in swallowing function in Friedreich ataxia over 12 months

Dysphagia (swallowing impairment) is present in 98% of individuals with Friedreich ataxia (FRDA) and is characterized by lingual and pharyngeal dysfunction (manifesting in impaired bolus preparation and transfer, and post-swallow residue in the mouth and pharynx), delayed swallow initiation, and entry of material into the airway (penetration/aspiration). Dysphagia severity correlates with disease severity and duration however no longitudinal studies describe changes in function in FRDA. The aim of this study was to investigate the progression of dysphagia in FRDA over one year. Fifty-nine individuals with FRDA and confirmed dysphagia were recruited and 23 of them underwent a second assessment 12 months later. Assessments of swallowing related quality of life, oral motor function (Frenchay Dysarthria Assessment 2nd Ed [FDA-2]) and functional swallowing via videofluoroscopy were conducted.

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Excision of the expanded GAA repeats corrects cardiomyopathy phenotypes of iPSC-derived Friedreich's ataxia cardiomyocytes

Although FRDA symptoms typically afflict the nervous system, hypertrophic cardiomyopathy is the predominant cause of death. These studies were conducted using cardiomyocytes differentiated from induced pluripotent stem cells derived from control individuals, FRDA patients, and isogenic cells corrected by zinc finger nucleases-mediated excision of pathogenic expanded GAA repeats. This correction of the FXN gene removed the primary trigger of the transcription defect, upregulated frataxin expression, reduced pathological lipid accumulation observed in patient cardiomyocytes, and reversed gene expression signatures of FRDA cardiomyocytes. Transcriptome analyses revealed hypertrophy-specific expression signatures unique to FRDA cardiomyocytes, and emphasized similarities between unaffected and ZFN-corrected FRDA cardiomyocytes. Thus, the iPSC-derived FRDA cardiomyocytes exhibit various molecular defects characteristic for cellular models of cardiomyopathy that can be corrected by genome editing of the expanded GAA repeats. These results underscore the utility of genome editing in generating isogenic cellular models of FRDA and the potential of this approach as a future therapy for this disease.

Read the entire article HERE

Folding and Dynamics are Strongly pH-Dependent in a Psychrophile Frataxin

Protein dynamics, folding, and thermodynamics represent a central aspect of biophysical chemistry. pH, temperature, and denaturant perturbations inform our understanding of diverse contributors to stability and rates. In this work, a thermodynamic analysis using a combined experimental and computational approach to gain insights into the role of electrostatics in the folding reaction of a psychrophile frataxin variant from Psychromonas ingrahamii. The folding reaction is strongly modulated by pH with a single, narrow and well-defined transition state with ~80% compactness, ~70% electrostatic interactions and ~60% hydration shell compared to the native state (αD=0.82, αH=0.67 and αΔCp=0.59). Molecular dynamics simulations showed that these pH modulation could be explained by the fluctuations of two regions, rich in electrostatic contacts, whose dynamics are pH-dependent and motions are strongly correlated. Results presented herein contribute to the understanding of the stability and dynamics of this frataxin variant, pointing to an intrinsic feature of the family topology to support different folding mechanism.

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Exploring iron-binding to human frataxin and to selected Friedreich ataxia mutants by means of NMR and EPR spectroscopies

The neurodegenerative disease Friedreich ataxia results from a deficiency of frataxin, a mitochondrial protein. Most patients have a GAA expansion in the first intron of both alleles of frataxin gene, whereas a minority of them are heterozygous for the expansion and contain a mutation in the other allele. Frataxin has been claimed to participate in iron homeostasis and biosynthesis of FeS clusters, however its role in both pathways is not unequivocally defined. In this work we combined different advanced spectroscopic analyses to explore the iron-binding properties of human frataxin, as isolated and at the FeS clusters assembly machinery. For the first time we used EPR spectroscopy to address this key issue providing clear evidence of the formation of a complex with a low symmetry coordination of the metal ion. By 2D NMR, we confirmed that iron can be bound in both oxidation states, a controversial issue, and, in addition, we were able to point out a transient interaction of frataxin with a N-terminal 6his-tagged variant of ISCU, the scaffold protein of the FeS clusters assembly machinery. To obtain insights on structure/function relationships relevant to understand the disease molecular mechanism(s), we extended our studies to four clinical frataxin mutants. All variants showed a moderate to strong impairment in their ability to activate the FeS cluster assembly machinery in vitro, while keeping the same iron-binding features of the wild type protein. This supports the multifunctional nature of frataxin and the complex biochemical consequences of its mutations.

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