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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.


Defective palmitoylation of transferrin receptor triggers iron overload in Friedreich's ataxia fibroblasts

Frataxin deficiency in Friedreich's ataxia (FRDA) affects ISC-containing proteins and causes iron to accumulate in the brain and heart of FRDA patients. This study reports on abnormal cellular iron homeostasis in FRDA fibroblasts inducing a massive iron overload in the cytosol and mitochondria. The authors observe membrane transferrin receptor 1 (TfR1) accumulation, increased TfR1 endocytosis, and delayed transferrin recycling, ascribing this to impaired TfR1 palmitoylation. Frataxin deficiency is shown to reduce coenzyme A (CoA) availability for TfR1 palmitoylation. Finally, this study demonstrates that artesunate, CoA, and dichloroacetate improve TfR1 palmitoylation and decrease iron overload, paving the road for evidence-based therapeutic strategies at the actionable level of TfR1 palmitoylation in FRDA.

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DNA repair pathways are altered in neural cell models of frataxin deficiency

As part of the overall efforts to understand the molecular basis of neurodegeneration in Friedreich's ataxia (FRDA), a new human neural cell line with doxycycline-induced FXN knockdown was established. This cell line, hereafter referred to as iFKD-SY, is derived from the human neuroblastoma SH-SY5Y and retains the ability to differentiate into mature neuron-like cells. In both proliferating and differentiated iFKD-SY cells, the induction of FXN deficiency is accompanied by increases in oxidative stress and DNA damage, reduced aconitase enzyme activity, higher levels of p53 and p21, activation of caspase-3, and subsequent apoptosis. More interestingly, FXN-deficient iFKD-SY cells exhibit an important transcriptional deregulation in many of the genes implicated in DNA repair pathways. The levels of some crucial proteins involved in DNA repair appear notably diminished. Furthermore, similar changes are found in two additional neural cell models of FXN deficit: primary cultures of FXN-deficient mouse neurons and human olfactory mucosa stem cells obtained from biopsies of FRDA patients. These results suggest that the deficiency of FXN leads to a down-regulation of DNA repair pathways that synergizes with oxidative stress to provoke DNA damage, which may be involved in the pathogenesis of FRDA. Thus, a failure in DNA repair may be considered a shared common molecular mechanism contributing to neurodegeneration in a number of hereditary ataxias including FRDA.

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Replication-independent instability of Friedreich's ataxia GAA repeats during chronological aging

Nearly 50 hereditary diseases result from the inheritance of abnormally long repetitive DNA microsatellites. While it was originally believed that the size of inherited repeats is the key factor in disease development, it has become clear that somatic instability of these repeats throughout an individual's lifetime strongly contributes to disease onset and progression. Importantly, somatic instability is commonly observed in terminally differentiated, postmitotic cells, such as neurons. To unravel the mechanisms of repeat instability in nondividing cells, the investigators created an experimental system to analyze the mutability of Friedreich's ataxia (GAA)n repeats during chronological aging of quiescent Saccharomyces cerevisiae Unexpectedly, the predominant repeat-mediated mutation in nondividing cells was found to be large-scale deletions encompassing parts, or the entirety, of the repeat and adjacent regions. These deletions are caused by breakage at the repeat mediated by mismatch repair (MMR) complexes MutSβ and MutLα and DNA endonuclease Rad1, followed by end-resection by Exo1 and repair of the resulting double-strand breaks (DSBs) via nonhomologous end joining. The authors also observed repeat-mediated gene conversions as a result of DSB repair via ectopic homologous recombination during chronological aging. Repeat expansions accrue during chronological aging as well-particularly in the absence of MMR-induced DSBs. These expansions depend on the processivity of DNA polymerase δ while being counteracted by Exo1 and MutSβ, implicating nick repair. Altogether, these findings show that the mechanisms and types of (GAA)n repeat instability differ dramatically between dividing and nondividing cells, suggesting that distinct repeat-mediated mutations in terminally differentiated somatic cells might influence Friedreich's ataxia pathogenesis.

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Efficacy of echocardiography for differential diagnosis of left ventricular hypertrophy: special focus on speckle-tracking longitudinal strain

Left ventricular (LV) hypertrophy (LVH) is a frequent imaging finding in daily clinical practice, and its presence is associated with poor outcomes and ventricular arrhythmias. It is commonly detected in athletes, arterial hypertension, aortic stenosis, hypertrophic cardiomyopathy, cardiac amyloidosis, Fabry disease, or Friedreich's ataxia. Echocardiography plays an important role in detecting LVH and underlying causes in current clinical practice. While echocardiography is essential for the quantification and early detection of LV structural findings for various cardiovascular diseases, it has been reported that speckle-tracking echocardiographic parameters are also useful for the detection of early LV structural abnormalities. In particular, global longitudinal strain (GLS) assessed by two-dimensional speckle-tracking echocardiography is reportedly a sensitive marker for early subtle abnormalities of LV myocardial performance, helpful for the prediction of outcomes for various cardiac diseases, and superior to conventional echocardiographic indices. GLS is determined as the averaged peak longitudinal strain of 18 LV segments from standard apical views and can be assessed as a polar plot. This polar plot longitudinal strain mapping offers an intuitive visual overview of the global and regional LV longitudinal myocardial function status of various cardiomyopathies with LVH. This mapping is clinically practicable and the plot patterns obtainable as the result of further development of this technique for clinical practice provide clues to the etiology of cardiomyopathies. This article reviews the efficacy of echocardiography for differential diagnosis of LVH, with a special focus on the utility of speckle-tracking longitudinal strain.

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Dimethyl fumarate dose-dependently increases mitochondrial gene expression and function in muscle and brain of Friedreich's ataxia model mice

Dimethyl fumarate (DMF) dose-dependently increases mitochondrial gene expression and function in cells and might be considered as a therapeutic for inherited mitochondrial disease, including Friedreich's ataxia. Here the authors tested DMF's ability to dose-dependently increase mitochondrial function, mitochondrial gene expression (frataxin and cytochrome oxidase protein) and mitochondrial copy number in C57BL6 wild-type mice and the FXNKD mouse model of Friedreich's Ataxia. DMF was first dosed at 0-320 mg/kg in C57BL6 mice and the authors observed significant toxicity above 160 mg/kg orally, defining the Maximum Tolerated Dose, MTD. Oral dosing of C57BL6 mice in the range 0-160 mg/kg identified a maximum increase in aconitase activity and mitochondrial gene expression in brain and quadriceps at 110 mg/kg DMF, thus defining the Maximum Effective Dose, MED. The MED of DMF in mice overlaps the currently approved human-equivalent doses of DMF prescribed for Multiple Sclerosis (480 mg/day) and Psoriasis (720 mg/day). In the FXNKD mouse model of Friedreich's ataxia, which has a doxycycline-induced deficit of frataxin protein, the authors observed significant decreases of multiple mitochondrial parameters, including deficits in brain mitochondrial Complex 2, Complex 4, and aconitase activity, supporting the idea that frataxin deficiency reduces mitochondrial gene expression, mitochondrial functions and biogenesis. 110 mg/kg oral DMF rescued these enzyme activities in brain and rescued frataxin and cytochrome oxidase expression in brain, cerebellum and quadriceps muscle of the FXNKD mouse model. Taken together, these results support the idea of using fumarate-based molecules to treat Friedreich's ataxia or other mitochondrial diseases.

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