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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.

MR imaging and spectroscopy in degenerative ataxias: toward multimodal, multisite, multistage monitoring of neurodegeneration

Degenerative ataxias are rare and currently untreatable movement disorders, primarily characterized by neurodegeneration in the cerebellum and brainstem. The authors highlight MRI studies with the most potential for utility in pending ataxia trials and underscore advances in disease characterization and diagnostics in the field. With availability of advanced MRI acquisition methods and specialized software dedicated to the analysis of MRI of the cerebellum, patterns of cerebellar atrophy in different degenerative ataxias are increasingly well defined. The field further embraced rigorous multimodal investigations to study network-level microstructural and functional brain changes and their neurochemical correlates. MRI and magnetic resonance spectroscopy were shown to be more sensitive to disease progression than clinical scales and to detect abnormalities in premanifest mutation carriers. Magnetic resonance techniques are increasingly well placed for characterizing the expression and progression of degenerative ataxias. The most impactful work has arguably come through multi-institutional studies that monitor relatively large cohorts, multimodal investigations that assess the sensitivity of different measures and their interrelationships, and novel imaging approaches that are targeted to known pathophysiology (e.g., iron and spinal imaging in Friedreich ataxia). These multimodal, multi-institutional studies are paving the way to clinical trial readiness and enhanced understanding of disease in degenerative ataxias.

Read the entire article HERE

Cardiolipin-deficient cells have decreased levels of the iron-sulfur biogenesis protein frataxin

Cardiolipin (CL) is the signature phospholipid of mitochondrial membranes, where it is synthesized locally and plays an important role in mitochondrial bioenergetics. Previous studies in the yeast model have indicated that CL is required for optimal iron homeostasis, which is disrupted by a mechanism not yet determined in the yeast CL mutant, crd1Δ. This finding has implications for the severe genetic disorder, Barth syndrome (BTHS), in which CL metabolism is perturbed because of mutations in the CL-remodeling enzyme, tafazzin. Here, we investigate the effects of tafazzin-deficiency on iron homeostasis in the mouse myoblast model of BTHS, TAZ-KO (tafazzin knockout) cells. Similarly to CL-deficient yeast cells, TAZ-KO cells exhibited elevated sensitivity to iron as well as to H2O2, which was alleviated by the iron chelator deferoxamine. TAZ-KO cells exhibited increased expression of the iron exporter ferroportin and decreased expression of the iron importer transferrin receptor, likely reflecting a regulatory response to elevated mitochondrial iron. Reduced activities of mitochondrial iron-sulfur cluster (Fe-S) enzymes suggested that the mechanism underlying perturbation of iron homeostasis was defective Fe-S biogenesis. This study showed decreased levels of Yfh1/frataxin, an essential component of the Fe-S biogenesis machinery, in mitochondria from TAZ-KO mouse cells and in CL-deleted yeast crd1Δ cells, indicating that the role of CL in Fe-S biogenesis is highly conserved. Yeast crd1Δ cells exhibited decreased processing of the Yfh1 precursor upon import, which likely contributes to the iron homeostasis defects. Implications for understanding the pathogenesis of BTHS are discussed.

Read the entire article HERE

Compound heterozygosity for an expanded (GAA) and a (GAAGGA) repeat at FXN locus: from a diagnostic pitfall to potential clues to the pathogenesis of Friedreich ataxia

Friedreich's ataxia (FRDA) is usually due to a homozygous GAA expansion in intron 1 of the frataxin (FXN) gene. Rarely, uncommon molecular rearrangements at the FXN locus can cause pitfalls in the molecular diagnosis of FRDA. Here the authors describe a family whose proband was affected by late-onset Friedreich's ataxia (LOFA); long-range PCR (LR-PCR) documented two small expanded GAA alleles both in the proband and in her unaffected younger sister, who therefore received a diagnosis of pre-symptomatic LOFA. Later studies, however, revealed that the proband's unaffected sister, as well as their healthy mother, were both carriers of an expanded GAA allele and an uncommon (GAAGGA)66-67 repeat mimicking a GAA expansion at the LR-PCR that was the cause of the wrong initial diagnosis of pre-symptomatic LOFA. Extensive studies in tissues from all the family members, including LR-PCR, assessment of methylation status of FXN locus, MboII restriction analysis and direct sequencing of LR-PCR products, analysis of FXN mRNA, and frataxin protein expression, support the virtual lack of pathogenicity of the rare (GAAGGA)66-67 repeat, also providing significant data about the modulation of epigenetic modifications at the FXN locus. Overall, this report highlights a rare but possible pitfall in FRDA molecular diagnosis, emphasizing the need of further analysis in case of discrepancy between clinical and molecular data.

Read the entire article HERE

Trinucleotide Repeat Disorders

Trinucleotide repeat disorders consist of a group of human diseases, which are a result of an abnormal expansion of repetitive sequences and primarily affect the nervous system. These occur during various stages of human development. Repetitive sequences, scattered in the microsatellite regions, usually account for about 30% of the human genome. In a normal person, the main purpose of various lengths of repetitive DNA is to allow for evolutionary plasticity. However, when these repeats extend beyond the code for a viable physiological protein, the expression of this aberrant segment is suppressed. After a certain threshold number, this suppression is lost, and an aberrant protein is coded for, which gives rise to either a functional or a non-functional protein, thereby giving rise to a 'gain of function' or 'loss of function' mutation. With every generation, the number of repeats increases drastically, and the age at which the patient presents is inversely related to the number of expansions. The severity, on the other hand, worsens with every generation due to a larger repeat sequence. Thus, the inheritance pattern of the repeat expansion diseases is evidence of the dynamic nature of these mutations and is termed as 'anticipation'. Myotonic dystrophy (DM), Huntington disease, spinocerebellar ataxia, Friedreich ataxia, and fragile X syndrome fall under the spectrum of trinucleotide repeat disorders. This article will study the various parameters of trinucleotide repeat disorders by reviewing in detail the five most commonly studied disorders, as listed above.

Read the entire article HERE

Stress-induced Mouse Model of the Cardiac Manifestations of Friedreich's Ataxia Corrected by AAV-mediated Gene Therapy

Although cardiac dysfunction is the most common cause of mortality in Friedreich's ataxia (FA), the cardiac disease remains subclinical for most of the clinical course because the neurologic disease limits muscle oxygen demands. Previous FXN knockout mouse models exhibit fatal cardiomyopathy similar to human FA but in contrast to the human condition, untreated mice become moribund by 2 months of age unlike humans where the cardiac disease often does not manifest until the 3rd decade. The study was designed to create a mouse model for early FA disease relevant to the time for which a gene therapy would likely be most effective. To generate a cardiac-specific mouse model of FA cardiomyopathy similar to the human disease, we used a cardiac promoter (αMyhc) driving Cre-recombinase cardiac-specific excision of FXN exon 4 to generate a mild cardiac-specific FA model that is normal at rest but exhibits the cardiac phenotype with stress. The hearts of αMyhc mice had decreased levels of FXN and activity of mitochondrial complex II/complex IV respiratory chain. At rest, the αMyhc mice exhibited normal cardiac function as assessed by echocardiographic assessment of ejection fraction and fractional shortening, but when the heart was stressed chemically with dobutamine, αMyhc mice compared to littermate control mice had a 62% reduction in stress ejection fraction (p0.07). These αMyhc mice provide an ideal model to study long-term cardiac complications due to FA and AAV-mediated gene therapy correction of stress-induced cardiac phenotypes typical of human FA.

Read the entire article HERE

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