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Defects in mitochondrial axonal transport and membrane potential without increased reactive oxygen species production in a Drosophila model of Friedreich ataxia.

ABSTRACT: Friedreich ataxia, a neurodegenerative disorder resulting from frataxin deficiency, is thought to involve progressive cellular damage from oxidative stress. In Drosophila larvae with reduced frataxin expression (DfhIR), we evaluated possible mechanisms of cellular neuropathology by quantifying mitochondrial axonal transport, membrane potential (MMP), and reactive oxygen species (ROS) production in the DfhIR versus wild-type nervous system throughout development. Although dying-back neuropathy in DfhIR larvae did not occur until late third instar, reduced MMP was already apparent at second instar in the cell bodies, axons and neuromuscular junctions (NMJs) of segmental nerves. Defects in axonal transport of mitochondria appeared late in development in distal nerve of DfhIR larvae, with retrograde movement preferentially affected. As a result, by late third instar the neuromuscular junctions (NMJs) of DfhIR larvae accumulated a higher density of mitochondria, many of which were depolarized. Notably, increased ROS production was not detected in any neuronal region or developmental stage in DfhIR larvae. However, when challenged with antimycin A, neurons did respond with a larger increase in ROS. We propose that pathology in the frataxin-deficient nervous system involves decreased MMP and ATP production followed by failures of mitochondrial transport and NMJ function.

SUBMITTER: Shidara Y

PROVIDER: S-EPMC2943153 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Defects in mitochondrial axonal transport and membrane potential without increased reactive oxygen species production in a Drosophila model of Friedreich ataxia.

Shidara Yujiro Y Hollenbeck Peter J PJ

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100801 34

Friedreich ataxia, a neurodegenerative disorder resulting from frataxin deficiency, is thought to involve progressive cellular damage from oxidative stress. In Drosophila larvae with reduced frataxin expression (DfhIR), we evaluated possible mechanisms of cellular neuropathology by quantifying mitochondrial axonal transport, membrane potential (MMP), and reactive oxygen species (ROS) production in the DfhIR versus wild-type nervous system throughout development. Although dying-back neuropathy in ...[more]

PMID: 20739558

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Project description:In patients with Friedreich ataxia, structural MRI is typically used to detect abnormalities primarily in the brainstem, cerebellum, and spinal cord. The aim of the present study was to additionally investigate possible metabolic changes in Friedreich ataxia using in vivo sodium MRI that may precede macroanatomical alterations, and to explore potential associations with clinical parameters of disease progression. Tissue sodium concentration across the whole brain was estimated from sodium MRI maps acquired at 3 T and compared between 24 patients with Friedreich ataxia (21-57 years old, 13 females) and 23 controls (21-60 years old, 12 females). Tensor-based morphometry was used to assess volumetric changes. Total sodium concentrations and volumetric data in brainstem and cerebellum were correlated with clinical parameters, such as severity of ataxia, activity of daily living and disability stage, age, age at onset, and disease duration. Compared to controls, patients showed reduced brain volume in the right cerebellar lobules I-V (difference in means: -0.039% of total intracranial volume [TICV]; Cohen's d = 0.83), cerebellar white matter (WM) (-0.105%TICV; d = 1.16), and brainstem (-0.167%TICV; d = 1.22), including pons (-0.102%TICV; d = 1.00), medulla (-0.036%TICV; d = 1.72), and midbrain (-0.028%TICV; d = 1.05). Increased sodium concentration was additionally detected in the total cerebellum (difference in means: 2.865 mmol; d = 0.68), and in several subregions with highest effect sizes in left (5.284 mmol; d = 1.01) and right cerebellar lobules I-V (5.456 mmol; d = 1.00), followed by increases in the vermis (4.261 mmol; d = 0.72), and in left (2.988 mmol; d = 0.67) and right lobules VI-VII (2.816 mmol; d = 0.68). In addition, sodium increases were also detected in all brainstem areas (3.807 mmol; d = 0.71 to 5.42 mmol; d = 1.19). After controlling for age, elevated total sodium concentrations in right cerebellar lobules IV were associated with younger age at onset (r = -0.43) and accordingly with longer disease duration in patients (r = 0.43). Our findings support the potential of in vivo sodium MRI to detect metabolic changes of increased total sodium concentration in the cerebellum and brainstem, the key regions in Friedreich ataxia. In addition to structural changes, sodium changes were present in cerebellar hemispheres and vermis without concomitant significant atrophy. Given the association with age at disease onset or disease duration, metabolic changes should be further investigated longitudinally and in larger cohorts of early disease stages to determine the usefulness of sodium MRI as a biomarker for early neuropathological changes in Friedreich ataxia and efficacy measure for future clinical trials.

Dataset Information

Defects in mitochondrial axonal transport and membrane potential without increased reactive oxygen species production in a Drosophila model of Friedreich ataxia.

Publications

Defects in mitochondrial axonal transport and membrane potential without increased reactive oxygen species production in a Drosophila model of Friedreich ataxia.

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