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Genetic and Physiological Studies in Friedreich's Ataxia

Brown, Alexander F.; (2019) Genetic and Physiological Studies in Friedreich's Ataxia. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

This thesis combines genetic and physiological studies of Friedreich’s ataxia (FRDA), an autosomal recessive disorder caused by a GAA triplet expansion mutation leading to a deficiency of the protein frataxin. This gives rise to a complex pathophysiology that affects not only the nervous system but also cardiac function, with the majority of FRDA patients dying from heart-related complications. In the genetic study, a sample of 2000 clinically undiagnosed ataxia cases referred to the National Hospital for Neurology and Neurosurgery (NHNN) over a 20-year period and who had not been previously screened for FRDA, were screened for the presence of any of the known FRDA mutations. Only 3 FRDA-positive cases were found, all conforming to the regular FRDA genotype of homozygous GAA triplet repeat expansion. These findings indicated the reliability of current FRDA diagnostic method and increased understanding of the FRDA genotypephenotype correlation among atypical FRDA cases, such as late-onset FRDA. In the physiological study, I studied the unexplored role of Ca2+ dysregulation in FRDA heart pathology. Frataxin was knocked-down in neonatal and adult FRDA-like cardiomyocyte models and Ca2+ homeostasis investigated. Both revealed a decreased Ca2+ sarcoplasmic reticulum (SR) content, combined with increased cellular and mitochondrial ROS levels. These data were confirmed in primary heart cells from well-established FRDA mouse models, such as the YG8R model. This was linked to increased leakage from the ryanodine receptors (RyR), causing Ca2+ to exit the SR, indicating a possible RyR potentiation in FRDA model heart cells due to frataxin deficiency. Together, these studies may lead to a better understanding of the impact of genetics on the FRDA clinical phenotype, and also widen our knowledge of the underlying mechanisms of the disease, with particular focus on the impact on Ca2+ signaling in heart cells affected by reduced frataxin.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Genetic and Physiological Studies in Friedreich's Ataxia
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
URI: https://discovery.ucl.ac.uk/id/eprint/10073013
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