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FARA Funded Research

Your generous support has funded all the research listed below.


For more information on FARA-funded research & scientists, please visit FARA Supported Research, Active Clinical Trials and the Featured Scientist.

Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich's ataxia

Friedreich's ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a GAA repeat expansion within the FXN gene, which downregulates frataxin, leading to abnormal mitochondrial iron accumulation, which may in turn cause changes in mitochondrial function. Although, many studies of FRDA patients and mouse models have been conducted in the past two decades, the role of frataxin in mitochondrial pathophysiology remains elusive. Are the mitochondrial abnormalities only a side effect of the increased accumulation of reactive iron, generating oxidative stress? Or does the progressive lack of iron-sulphur clusters (ISCs), induced by reduced frataxin, cause an inhibition of the electron transport chain complexes (CI, II and III) leading to reactive oxygen species escaping from oxidative phosphorylation reactions? To answer these crucial questions, we have characterised the mitochondrial pathophysiology of a group of disease-relevant and readily accessible neurons, cerebellar granule cells, from a validated FRDA mouse model.

Read the entire article HERE

Abundance and Significance of Iron, Zinc, Copper, and Calcium in the Hearts of Patients With Friedreich Ataxia

Cardiomyopathy is a frequent cause of death in patients with Friedreich ataxia (FA), and a characteristic pathological feature is the focal accumulation of iron (Fe) in cardiomyocytes. This restricted localization of the metal contrasts with the diffuse cardiac Fe overload in hemochromatosis and transfusion siderosis. Nevertheless, heart Fe in FA contributes to cardiomyocyte necrosis, inflammation, and scarring as the disease progresses. A putative mechanism of cardiomyopathy in FA is Fe-mediated oxidative damage. Two other transition metals zinc (Zn) and copper (Cu), are diffusely distributed throughout normal hearts and the hearts of patients with FA.

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Dorsal root ganglia in Friedreich ataxia: satellite cell proliferation and inflammation

Dorsal root ganglia (DRG) are highly vulnerable to frataxin deficiency in Friedreich ataxia (FA). An immunohistochemical and immunofluorescence study of DRG in 15 FA cases and 12 controls revealed that FA causes major primary changes in satellite cells and inflammatory destruction of neurons. Reaction product of the cytoplasmic markers and laminin confirmed proliferation of satellite cells and processes into multiple perineuronal layers and residual nodules. The formation of connexin 43-reactive gap junctions between satellite cells was strongly upregulated. Proliferating satellite cells in FA displayed many more frataxin- and ATP5B-reactive mitochondria than normal. Monocytes entered into the satellite cell layer, appeared to penetrate neuronal plasma membranes, and infiltrated residual nodules. Satellite cells and IBA1-reactive monocytes displayed upregulated ferritin biosynthesis, which was most likely due to leakage of iron from dying neurons.

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Comorbid Medical Conditions in Friedreich Ataxia: Association With Inflammatory Bowel Disease and Growth Hormone Deficiency

Friedreich ataxia is a progressive degenerative disease with neurologic and cardiac involvement. This study characterizes comorbid medical conditions in a large cohort of patients with Friedreich ataxia. Patient diagnoses were collected in a large natural history study of 641 subjects. Prevalence of diagnoses in the cohort with Friedreich ataxia was compared with prevalence in the population without Friedreich ataxia. Ten patients (1.6%) had inflammatory bowel disease, 3.5 times more common in this cohort of individuals with Friedreich ataxia than in the general population. Four subjects were growth hormone deficient, reflecting a prevalence in Friedreich ataxia that is 28 times greater than the general population. The present study identifies specific diagnoses not traditionally associated with Friedreich ataxia that are found at higher frequency in this disease. These associations could represent coincidence, shared genetic background, or potentially interactive disease mechanisms with Friedreich ataxia.

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Effects of Genetic Severity on Glucose Homeostasis in Friedreich Ataxia

Abstract
INTRODUCTION:
Friedreich ataxia (FRDA) leads to increased risk of diabetes. Less is known regarding the dynamics of glucose homeostasis in FRDA, the influence of disease features, and the utility of oral-based metrics for capturing metabolic dysfunction.

METHODS:
To examine these dynamics, we analyzed oral and intravenous glucose tolerance test data in 42 non-diabetic patients with FRDA.

RESULTS:
Patients showed high insulin responsiveness to glucose and low insulin sensitivity. Genetic severity predicted overall metabolic impairment: individuals with longer guanineadenine-adenine (GAA) repeats on the shorter allele showed a lower disposition index. Genetic severity did not predict any other variables. Measures of disposition index from intravenous and oral glucose tolerance testing did not correlate well, possibly reflecting divergent responses to oral and IV glucose loads.

DISCUSSION:
FRDA patients demonstrate abnormal compensatory activity for managing glucose. Genetic severity impacts the global homeostatic profile, whereas relative contributions of insulin secretion and action vary from patient-to-patient. This article is protected by copyright. All rights reserved.

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