Deficiency of iron‑sulfur (FeS) clusters promotes metabolic rewiring of the endothelium and the development of pulmonary hypertension (PH) in vivo. Joining a growing number of FeS biogenesis proteins critical to pulmonary endothelial function, recent data highlighted that frataxin (FXN) reduction drives Fe-S-dependent genotoxic stress and senescence across multiple types of pulmonary vascular disease. Trinucleotide repeat mutations in the FXN gene cause Friedreich's ataxia, a disease characterized by cardiomyopathy and neurodegeneration. These tissue-specific phenotypes have historically been attributed to mitochondrial reprogramming and oxidative stress. Whether FXN coordinates both nuclear and mitochondrial processes in the endothelium is unknown. Here, the authors aim to identify the mitochondria-specific effects of FXN deficiency in the endothelium that predispose to pulmonary hypertension. These data highlight an Fe-S-driven metabolic shift separate from previously described replication stress whereby FXN knockdown diminished mitochondrial respiration and increased glycolysis and oxidative species production. In turn, FXN-deficient endothelial cells had increased vasoconstrictor production (EDN1) and decreased nitric oxide synthase expression (NOS3). These data were observed in primary pulmonary endothelial cells after pharmacologic inhibition of FXN, mice carrying a genetic endothelial deletion of FXN, and inducible pluripotent stem cell-derived endothelial cells from patients with FXN mutations. Altogether, this study indicates FXN is an upstream driver of pathologic aberrations in metabolism and genomic stability. Moreover, this study highlights FXN-specific vasoconstriction in vivo, prompting future studies to investigate available and novel PH therapies in contexts of FXN deficiency.
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Scientific News
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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.
Frataxin deficiency disrupts mitochondrial respiration and pulmonary endothelial cell function
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Adenosine Improves Mitochondrial Function and Biogenesis in Friedreich's Ataxia Fibroblasts Following L-Buthionine Sulfoximine-Induced Oxidative Stress
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Adenosine is a nucleoside that is widely distributed in the central nervous system and acts as a central excitatory and inhibitory neurotransmitter in the brain. The protective role of adenosine in different pathological conditions and neurodegenerative diseases is mainly mediated by adenosine receptors. However, its potential role in mitigating the deleterious effects of oxidative stress in Friedreich's ataxia (FRDA) remains poorly understood. The authors aimed to investigate the protective effects of adenosine against mitochondrial dysfunction and impaired mitochondrial biogenesis in L-buthionine sulfoximine (BSO)-induced oxidative stress in dermal fibroblasts derived from an FRDA patient. The FRDA fibroblasts were pre-treated with adenosine for 2 h, followed by 12.50 mM BSO to induce oxidative stress. Cells in medium without any treatments or pre-treated with 5 µM idebenone served as the negative and positive controls, respectively. Cell viability, mitochondrial membrane potential (MMP), aconitase activity, adenosine triphosphate (ATP) level, mitochondrial biogenesis, and associated gene expressions were assessed. Disruption of mitochondrial function and biogenesis and alteration in gene expression patterns in BSO-treated FRDA fibroblasts were observed. Pre-treatment with adenosine ranging from 0-600 µM restored MMP, promoted ATP production and mitochondrial biogenesis, and modulated the expression of key metabolic genes, namely nuclear respiratory factor 1 (NRF1), transcription factor A, mitochondrial (TFAM), and NFE2-like bZIP transcription factor 2 (NFE2L2). This study demonstrated that adenosine targeted mitochondrial defects in FRDA, contributing to improved mitochondrial function and biogenesis, leading to cellular iron homeostasis. Therefore, the authors suggest a possible therapeutic role for adenosine in FRDA.
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Short-read genome sequencing allows 'en route' diagnosis of patients with atypical Friedreich ataxia
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Pre-selection of the correct genetic diagnostic method according to the presumed underlying mutational mechanism has been key in current ataxia routine diagnostics: short-tandem repeat-expansions (STRs) are missed by standard next-generation sequencing (NGS) panel-based approaches; and while exome sequencing (ES)-based STR analyses are now being considered standard for clinical routine, they still show only moderate specificity for exonic STRs and—by design—fail almost completely for most of the intronic STRs in ataxias. This pre-selection of genetic diagnostics, e.g. direct fragment length analysis for FA, however, is led by clinical suspicion based on the main clinical phenotype and additional relevant information (such as e.g. the supposed inheritance mode). However, this pre-selection is vulnerable to bias. By a series of three distinct cases of atypical FA, the authors here showcase how the introduction of short-read genome sequencing (SR-GS) allows to overcome these biases in the work-up of complex ataxias, as it allows to detect even intronic STRs (i) “en route”, i.e. with detection not requiring any primary direct gene analysis; and (ii) in a phenotype-independent fashion”, i.e. also for those atypical phenotypic presentations where the corresponding gene and mutational mechanism had not been part of the prior differential clinical diagnosis.
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Epidemiology of ataxia and hereditary spastic paraplegia in Spain: a cross-sectional study
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This study aimed to determine the prevalence of ataxia and hereditary spastic paraplegia in Spain in 2019. The authors conducted a cross-sectional, multicentre, retrospective, descriptive study of patients with ataxia and hereditary spastic paraplegia in Spain between March 2018 and December 2019. Data from a total of 1933 patients from 11 autonomous communities, provided by 47 neurologists or geneticists were gathered. Mean (SD) age in our sample was 53.64 (20.51) years; 938 patients were men (48.5%) and 995 were women (51.5%). The genetic defect was unidentified in 920 patients (47.6%). A total of 1371 patients (70.9%) had ataxia and 562 (29.1%) had hereditary spastic paraplegia. Prevalence rates for ataxia and hereditary spastic paraplegia were estimated at 5.48 and 2.24 cases per 100 000 population, respectively. The most frequent type of dominant ataxia in our sample was SCA3, and the most frequent recessive ataxia was Friedreich ataxia. The most frequent type of dominant hereditary spastic paraplegia in our sample was SPG4, and the most frequent recessive type was SPG7. In this sample, the estimated prevalence of ataxia and hereditary spastic paraplegia was 7.73 cases per 100 000 population. This rate is similar to those reported for other countries. Genetic diagnosis was not available in 47.6% of cases. Despite these limitations, this study provides useful data for estimating the necessary healthcare resources for these patients, raising awareness of these diseases, determining the most frequent causal mutations for local screening programs, and promoting the development of clinical trials.
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Neuropsychiatric symptoms in spinocerebellar ataxias and Friedreich ataxia
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Apart from its role in motor coordination, the importance of the cerebellum in cognitive and affective processes has been recognized in the past few decades. Spinocerebellar ataxias (SCA) and Friedreich ataxia (FRDA) are rare neurodegenerative diseases of the cerebellum presenting mainly with a progressive loss of gait and limb coordination, dysarthria, and other motor disturbances, but also a range of cognitive and neuropsychiatric symptoms. This narrative review summarizes the current knowledge on neuropsychiatric impairment in SCA and FRDA. The authors discuss the prevalence, clinical features and treatment approaches in the most commonly reported domains of depression, anxiety, apathy, agitation and impulse dyscontrol, and psychosis. Since these symptoms have a considerable impact on patients' quality of life, further research is mandated to improve the detection and treatment options of neuropsychiatric co-morbidities in ataxia patients.
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- Omaveloxolone (Skyclarys™) for patients with Friedreich's ataxia
- Omaveloxolone: First Approval
- Pseudodominance in Friedreich Ataxia-Impact of High Prevalence of Carriers and Intrafamilial Clinical Variation
- Auditory neuropathy in mice and humans with Friedreich ataxia
- Skeletal muscle transcriptomics dissects the pathogenesis of Friedreich's Ataxia