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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.


Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich's ataxia patient cells

The molecular mechanisms of reduced frataxin (FXN) expression in Friedreich's ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, the authors identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN-GAA-Luciferase repeat expansion genomic DNA reporter model of FRDA, the Structural Genomics Consortium epigenetic probe collection was screened. This study found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by approximately 1.5-fold in the reporter cell line. In several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells A-196 increased FXN expression by up to 2-fold, an effect not seen in wild-type cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4-7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogues were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, these results suggest that histone methylation is important in the regulation of FXN expression, and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.

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Assessment of Ataxia Rating Scales and Cerebellar Functional Tests: Critique and Recommendations

This study assessed the clinimetric properties of ataxia rating scales and functional tests, and made recommendations regarding their use. A systematic literature search was conducted to identify the instruments used to rate ataxia symptoms. The identified rating scales and functional ability tests were reviewed and ranked by the panel as "recommended," "suggested," or "listed" for the assessment of patients with discrete cerebellar disorders, using previously established criteria. 14 instruments (9 rating scales and 5 functional tests) were reviewed. "Recommended" rating scales for the assessment of symptoms severity were: for Friedreich's ataxia, the Friedreich's Ataxia Rating Scale, the International Cooperative Ataxia Rating Scale (ICARS), and the Scale for the Assessment and Rating of Ataxia (SARA); for spinocerebellar ataxias, ICARS and SARA; for ataxia telangiectasia: ICARS and SARA; for brain tumors, SARA; for congenital disorder of glycosylation-phosphomannomutase-2 deficiency, ICARS; for cerebellar symptoms in multiple sclerosis, ICARS; for cerebellar symptoms in multiple system atrophy: Unified Multiple System Atrophy Rating Scale and ICARS; and for fragile X-associated tremor ataxia syndrome, ICARS. "Recommended" functional tests were: for Friedreich's ataxia, Ataxia Functional Composite Score and Composite Cerebellar Functional Severity Score; and for spinocerebellar ataxias, Ataxia Functional Composite Score, Composite Cerebellar Functional Severity Score, and SCA Functional Index. Some "recommended" scales and functional tests for the assessment of patients with major hereditary ataxias and other cerebellar disorders were identified. The main limitations of these instruments include the limited assessment of patients in the more severe end of the spectrum and children. Further research in these populations is warranted.

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Quantitative Assessment of Friedreich Ataxia through the self-drinking activity

The progression of neurodegenerative conditions can be effectively monitored and improved by using objective assessments. The conditions such as Friedreich Ataxia (FA) are clinically assessed by means of subjective measures commonly practised in clinics. Here, we propose a device capable of measuring ataxia, in the form of a `cup' capable of sensing certain kinematic parameters of interest while engaging in an activity that is closely related to daily living. In this study, the functional task of 'drinking' was utilised to diagnose participants with FA and capture features in terms of diagnosis (separation) and correlation with the clinical scales. Frequency domain analysis was incorporated enabling the classification of control subjects and FA patients to an accuracy of 88% with a correlation of 90% with the clinical scores.

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Oxidative stress-dependent frataxin inhibition mediated alcoholic hepatocytotoxicity through ferroptosis

Alcoholic liver disease (ALD) is one of the severe liver diseases, resulting in high morbidity and mortality. However, frataxin, a mitochondrial protein mainly participating in iron homeostasis and oxidative stress, remains uncertain in the pathogenesis of ALD. In the present study, the role of frataxin in ALD was investigated. Ethanol (100 mM) decreased frataxin expression at 48 and 72 h in HepG2. Dramatically, in HepG2 overexpressing cytochrome P450 2E1 (HepG2CYP2E1+/+), frataxin level was down-regulated with ethanol stimulation at 12 h. Moreover, chronically feeding ethanol to mice via Lieber-DeCarli liquid diet (30 % of total calories) for 15 weeks significantly inhibited frataxin expression. Ferroptosis signature proteins were dysregulated, accompanied by mitochondrial damage of morphology, enhanced malondialdehyde and decreased glutathione in the liver, as well as accumulation of reactive oxygen species and mitochondrial labile iron pool in primary hepatocytes. Notably, proteomics screening of frataxin deficient-HepG2 further suggested frataxin was associated with ferroptosis. Furthermore, the ferroptosis inhibitor ferrostatin-1 blocked the increase of lactate dehydrogenase release by ethanol in HepG2CYP2E1+/+. Most importantly, frataxin deficiency enhanced ferroptosis driven by ethanol via evaluating the levels of lactate dehydrogenase, cell morphological changes, mitochondrial labile iron pool, and lipid peroxidation. Conversely, restoring frataxin alleviated the sensitivity to ferroptosis. In addition, frataxin overexpression mitigated the sensitivity of ethanol-induced ferroptosis in HepG2CYP2E1+/+. Collectively, this study revealed that frataxin-mediated ferroptosis contributed to ALD, highlighting a potential therapeutic strategy for ALD.

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Mechanistic concepts of iron-sulfur protein biogenesis in Biology

Iron-sulfur (Fe/S) proteins are present in virtually all living organisms and are involved in numerous cellular processes such as respiration, photosynthesis, metabolic reactions, nitrogen fixation, radical biochemistry, protein synthesis, antiviral defense, and genome maintenance. Their versatile functions may go back to the proposed role of their Fe/S cofactors in the origin of life as efficient catalysts and electron carriers. More than two decades ago, it was discovered that the in vivo synthesis of cellular Fe/S clusters and their integration into polypeptide chains requires assistance by complex proteinaceous machineries, despite the fact that Fe/S proteins can be assembled chemically in vitro. In prokaryotes, three Fe/S protein biogenesis systems are known; ISC, SUF, and the more specialized NIF. The former two systems have been transferred by endosymbiosis from bacteria to mitochondria and plastids, respectively, of eukaryotes. In their cytosol, eukaryotes use the CIA machinery for the biogenesis of cytosolic and nuclear Fe/S proteins. Despite the structural diversity of the protein constituents of these four machineries, general mechanistic concepts underlie the complex process of Fe/S protein biogenesis. This review provides a comprehensive and comparative overview of the various known biogenesis systems in Biology, and summarizes their common or diverging molecular mechanisms, thereby illustrating both the conservation and diverse adaptions of these four machineries during evolution and under different lifestyles. Knowledge of these fundamental biochemical pathways is not only of basic scientific interest, but is important for the understanding of human 'Fe/S diseases' and can be used in biotechnology.

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