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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.

Protoporphyrin IX Binds to Iron(II)-Loaded and to Zinc-Loaded Human FrataxinProtoporphyrin IX Binds to Iron(II)-Loaded and to Zinc-Loaded Human Frataxin

While frataxin association to other proteins has been extensively characterized up to the structural level, much less is known about the putative capacity of frataxin to interact with functionally related metabolites. Current knowledge about frataxin's capacity to coordinate metal ions is limited to iron (II and III). Here, the authors used NMR spectroscopy, Molecular Dynamics, and Docking approaches to demonstrate new roles of frataxin and showed that that frataxin also binds Zn2+ in a structurally similar way to Fe2+, but with lower affinity. Both Fe2+-loaded and Zn2+-loaded frataxins specifically associate to protoporphyrin IX with micromolar affinity, while apo-frataxin does not bind to the porphyrin. Protoporphyrin IX association to metal-loaded frataxin shares the binding epitope with ferrochelatase. These findings expand the plethora of relevant molecular targets for frataxin and may help to elucidate the yet unknown different roles that this protein exerts in iron regulation and metabolism.

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A wearable motion capture suit and machine learning predict disease progression in Friedreich's ataxia

Current gold-standard clinical scales in FA use simplistic behavioral assessments, which require 18- to 24-month-long trials to determine if therapies are beneficial. Here the author captured full-body movement kinematics from patients with wearable sensors, enabling them to define digital behavioral features based on the data from nine FA patients (six females and three males) and nine age- and sex-matched controls, who performed the 8-m walk (8-MW) test and 9-hole peg test (9 HPT). Machine learning was used to combine these features to longitudinally predict the clinical scores of the FA patients, and compared these with two standard clinical assessments, Spinocerebellar Ataxia Functional Index (SCAFI) and Scale for the Assessment and Rating of Ataxia (SARA). The digital behavioral features enabled longitudinal predictions of personal SARA and SCAFI scores 9 months into the future and were 1.7 and 4 times more precise than longitudinal predictions using only SARA and SCAFI scores, respectively. Unlike the two clinical scales, the digital behavioral features accurately predicted FXN gene expression levels for each FA patient in a cross-sectional manner. This work demonstrates how data-derived wearable biomarkers can track personal disease trajectories and indicates the potential of such biomarkers for substantially reducing the duration or size of clinical trials testing disease-modifying therapies and for enabling behavioral transcriptomics.

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Neurobehavioral deficits of mice expressing a low level of G127V mutant frataxin

A missense mutation, changing a glycine to valine at position 130 (G130V) in frataxin, is prevalent among the clinical variants in FRDA. Levels of mature FXN protein in FRDA G130V samples are reduced below those detected in samples harboring homozygous repeat expansions. Little is known regarding expression and function of endogenous FXN-G130V protein due to lack of reagents and models that can distinguish the mutant FXN protein from the wild-type FXN produced from the GAA-expanded allele. This group aimed to determine the effect of the G130V (murine G127V) mutation on Fxn expression and to define its multi-system impact in vivo. CRISPR/Cas9 was used to introduce the G127V missense mutation in the Fxn coding sequence and homozygous mice (FxnG127V/G127V) were generated. The G127V mutation was also introduced into a GAA repeat expansion FRDA mouse model (FxnGAA230/KO; KIKO) to generate a compound heterozygous strain (FxnG127V/GAA230). The investigators performed neurobehavioral tests on cohorts of WT and Fxn mutant animals at three-month intervals for one year, and collected tissue samples to analyze molecular changes during that time. The endogenous Fxn G127V protein is detected at much lower levels in all tissues analyzed from FxnG127V/G127V mice compared to age and sex-matched WT mice without differences in Fxn transcript levels. FxnG127V/G127V mice are significantly smaller than WT counterparts, but perform similarly in most neurobehavioral tasks. RNA sequencing analysis revealed reduced expression of genes in oxidative phosphorylation and protein synthesis, underscoring the metabolic consequences in our mouse model expressing extremely low levels of Fxn. Results of these studies provide insight into the unique pathogenic mechanism of the FXN G130V mechanism and the tolerable limit of Fxn/FXN expression in vivo.

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FXN gene methylation determines carrier status in Friedreich ataxia

Detection of the expanded GAA triplet-repeat (GAA-TRE) in the heterozygous state, occasionally technically challenging, is essential for diagnosing compound heterozygotes and asymptomatic carriers. The authors explored if the FRDA differentially methylated region (FRDA-DMR) in intron 1, which is hypermethylated in cis with the GAA-TRE, effectively detects heterozygous GAA-TRE. FXN DNA methylation was assayed by targeted bisulfite deep sequencing using the Illumina platform. FRDA-DMR methylation effectively identified a cohort of known heterozygous carriers of the GAA-TRE. In an individual with clinical features of FRDA, commercial testing showed a paternally inherited pathogenic FXN initiation codon variant but no GAA-TRE. Methylation in the FRDA-DMR effectively identified the proband, his mother and various maternal relatives as heterozygous carriers of the GAA-TRE, thus confirming the diagnosis of FRDA. FXN DNA methylation reliably detects the GAA-TRE in the heterozygous state and offers a robust alternative strategy to diagnose FRDA due to compound heterozygosity and to identify asymptomatic heterozygous carriers of the GAA-TRE.

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Cardiovascular Research in Friedreich Ataxia: Unmet Needs and Opportunities

The cardiomyopathy in FRDA is unlike the sarcomeric hypertrophic cardiomyopathies in that the hypertrophy is associated with massive mitochondrial proliferation within the cardiomyocyte rather than contractile protein overexpression. This is associated with atrial arrhythmias, apoptosis, and fibrosis over time, and patients often develop heart failure leading to premature death. The differences between this mitochondrial cardiomyopathy and the more common contractile protein hypertrophic cardiomyopathies can be a source of misunderstanding in the management of these patients. Although imaging studies have revealed much about the structure and function of the heart in this disease, we still lack an understanding of many important clinical and fundamental molecular events that determine outcome of the heart in FRDA. This review will describe the current basic and clinical understanding of the FRDA heart, and most importantly, identify major gaps in our knowledge that represent new directions and opportunities for research.

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