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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.



Application of Quantitative Motor Assessments in Friedreich Ataxia and Evaluation of Their Relation to Clinical Measures

As common clinical measures for Friedreich's ataxia (FRDA) can lack sensitivity, we explored whether (a) the quantitative motor assessments of the Q-Motor battery can enhance clinical characterisation of FRDA; (b) clinical measures can predict Q-Motor outcomes and (c) Q-Motor is sensitive to longitudinal change. At baseline 29 patients and 23 controls and in a 1-year follow-up 14 patients and 6 controls were included. The Q-Motor included lift (manumotography), finger tapping (digitomotography) and pronate/supinate (dysdiadochomotography) tasks. To model responses, a search of generalised linear models was conducted, selecting best fitting models, using demographic and clinical data as predictors. Predictors from selected models were used in linear mixed models to investigate longitudinal changes. Patients with FRDA performed worse than controls on most measures. Modelling of the pronate/supinate task was dominated by SCAFI (SCA functional index) subtasks, while tapping task and lift task models suggested a complex relationship with clinical measures. Longitudinal modelling implied minor changes from baseline to follow-up, while clinical scales mainly showed no change in this sample. Overall Q-Motor likely has favourable properties for assessing distinct motor aspects in severe FRDA as it can be administered in wheelchair-bound patients. Further longitudinal research is warranted to fully characterise its relation to routinely used measures and scales for FRDA.

Read the entire article HERE

Oral mobility reflects rate of progression in advanced Friedreich's ataxia

The objective was to identify a sensitive marker of disease progression in Friedreich's ataxia. This study prospectively evaluated speech, voice, and oromotor function in 40 patients at two time points. The mean disease duration was 20.8 ± 9.8 years and mean SARA score 23.7 ± 8.6 at baseline. Oral motor mobility, assessed by a combination of movements of the face, eyes, cheeks, lips, and tongue, decreased significantly after 1 year (P

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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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Nrf2 Induction Re-establishes a Proper Neuronal Differentiation Program in Friedreich's Ataxia Neural Stem Cells

This paper describes impairments in proliferation, stemness potential and differentiation in neural stem cells (NSCs) isolated from the embryonic cortex of the Frataxin Knockin/Knockout (KI/KO) mouse, a disease animal model whose slow-evolving phenotype makes it suitable to study pre-symptomatic defects that may manifest before the clinical onset. We demonstrate that enhancing the expression and activity of the antioxidant response master regulator Nrf2 ameliorates the phenotypic defects observed in NSCs, re-establishing a proper differentiation program.

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