Friedreichs ataxia (FRDA) is a progressive spinocerebellar ataxia (SCA) inherited as an autosomal recessive trait. The neurodegeneration, cardiomyopathy, diabetes mellitus and skeletal deformities characteristic to FRDA result from a deficiency in the mitochondrial protein frataxin. Frataxin chaperones iron to heme and iron-sulfur clusters and its deficiency causes mitochondrial iron accumulation and oxidative stress.<p> To address the effect of frataxin deficiency on mitochondrial iron chemistry, mitochondria were isolated from FRDA and control fibroblasts. X-ray absorption spectroscopy showed that ferrihydrite was the predominant form of iron in both. Near edge analysis showed that the ferrihydrite in the FRDA mitochondria resembled the highly organized ferrihydrite of ferritin. Western blotting confirmed that FRDA mitochondria had 3-fold more holoferritin containing stainable iron. I conclude that mitochondria from FRDA fibroblasts mineralize excess iron as ferrihydrite within mitochondrial ferritin.<p> To address how cellular iron dysregulation affected metal distribution in brain and spinal cord, a new synchrotron imaging technique, rapid-scanning x-ray fluorescence (RS-XRF) was employed and validated. Brain structures were readily identified by their unique metal content and distribution. This showed that RS-XRF could be used to reveal metal pathologies associated with diseases of metal metabolism such as FRDA. Since human FRDA tissues were not available for a detailed study, RS-XRF was employed to study the distribution of metals in normal cerebellum, a major site of FRDA-associated neurodegeneration, and to localize and quantify metals in the brain and spinal cord from a patient with a SCA of unknown aetiology. The motivation for this work is the prospect of future systematic studies on metal pathology in neurodegenerative diseases with direct application to FRDA. Novel findings arising from this work were the metal segmentation of the dentate nucleus, the high copper content of the olivary region and the different metal content of lesions at different stages of neurodegeneration. My results suggest that not only iron, but also copper and zinc may play a role in the physiopathology of neurodegeneration. Therefore, all three metals should be investigated in FRDA and other SCA of both known and unknown aetiologies to identify possible new therapeutic targets.

Friedreichs ataxia (FRDA) is a progressive spinocerebellar ataxia (SCA) inherited as an autosomal recessive trait. The neurodegeneration, cardiomyopathy, diabetes mellitus and skeletal deformities characteristic to FRDA result from a deficiency in the mitochondrial protein frataxin. Frataxin chaperones iron to heme and iron-sulfur clusters and its deficiency causes mitochondrial iron accumulation and oxidative stress.<p> To address the effect of frataxin deficiency on mitochondrial iron chemistry, mitochondria were isolated from FRDA and control fibroblasts. X-ray absorption spectroscopy showed that ferrihydrite was the predominant form of iron in both. Near edge analysis showed that the ferrihydrite in the FRDA mitochondria resembled the highly organized ferrihydrite of ferritin. Western blotting confirmed that FRDA mitochondria had 3-fold more holoferritin containing stainable iron. I conclude that mitochondria from FRDA fibroblasts mineralize excess iron as ferrihydrite within mitochondrial ferritin.<p> To address how cellular iron dysregulation affected metal distribution in brain and spinal cord, a new synchrotron imaging technique, rapid-scanning x-ray fluorescence (RS-XRF) was employed and validated. Brain structures were readily identified by their unique metal content and distribution. This showed that RS-XRF could be used to reveal metal pathologies associated with diseases of metal metabolism such as FRDA. Since human FRDA tissues were not available for a detailed study, RS-XRF was employed to study the distribution of metals in normal cerebellum, a major site of FRDA-associated neurodegeneration, and to localize and quantify metals in the brain and spinal cord from a patient with a SCA of unknown aetiology. The motivation for this work is the prospect of future systematic studies on metal pathology in neurodegenerative diseases with direct application to FRDA. Novel findings arising from this work were the metal segmentation of the dentate nucleus, the high copper content of the olivary region and the different metal content of lesions at different stages of neurodegeneration. My results suggest that not only iron, but also copper and zinc may play a role in the physiopathology of neurodegeneration. Therefore, all three metals should be investigated in FRDA and other SCA of both known and unknown aetiologies to identify possible new therapeutic targets.

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