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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder involving the progressive degeneration of motor neurons in the brain and spinal cord. Mitochondrial dysfunction plays a key role in ALS disease progression and has been observed in several ALS cellular and animal models. Here, we show that fibroblasts isolated from ALS cases with a Cu/Zn superoxide dismutase (SOD1) I113T mutation recapitulate these mitochondrial defects. Using a novel technique, which measures mitochondrial respiration and glycolytic flux simultaneously in living cells, we have shown that SOD1 mutation causes a reduction in mitochondrial respiration and an increase in glycolytic flux. This causes a reduction in adenosine triphosphate produced by oxidative phosphorylation and an increase in adenosine triphosphate produced by glycolysis. Switching the energy source from glucose to galactose caused uncoupling of mitochondria with increased proton leak in SOD1(I113T) fibroblasts. Assessment of the contribution of fatty acid oxidation to total respiration, suggested that fatty acid oxidation is reduced in SOD1 ALS fibroblasts, an effect which can be mimicked by starving the control cells of glucose. These results highlight the importance of understanding the interplay between the major metabolic pathways, which has the potential to lead to strategies to correct the metabolic dysregulation observed in ALS cases.
    Neurobiology of aging 12/2013; DOI:10.1016/j.neurobiolaging.2013.11.025
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    ABSTRACT: Objective Loss of function mutations in PINK1 typically lead to early onset Parkinson disease (PD). Zebrafish (Danio rerio) are emerging as a powerful new vertebrate model to study neurodegenerative diseases. We used a pink1 mutant (pink(-/-)) zebrafish line with a premature stop mutation (Y431*) in the PINK1 kinase domain to identify molecular mechanisms leading to mitochondrial dysfunction and loss of dopaminergic neurons in PINK1 deficiency. Methods The effect of PINK1 deficiency on the number of dopaminergic neurons, mitochondrial function, and morphology was assessed in both zebrafish embryos and adults. Genome-wide gene expression studies were undertaken to identify novel pathogenic mechanisms. Functional experiments were carried out to further investigate the effect of PINK1 deficiency on early neurodevelopmental mechanisms and microglial activation. ResultsPINK1 deficiency results in loss of dopaminergic neurons as well as early impairment of mitochondrial function and morphology in Danio rerio. Expression of TigarB, the zebrafish orthologue of the human, TP53-induced glycolysis and apoptosis regulator TIGAR, was markedly increased in pink(-/-) larvae. Antisense-mediated inactivation of TigarB gave rise to complete normalization of mitochondrial function, with resulting rescue of dopaminergic neurons in pink(-/-) larvae. There was also marked microglial activation in pink(-/-) larvae, but depletion of microglia failed to rescue the dopaminergic neuron loss, arguing against microglial activation being a key factor in the pathogenesis. InterpretationPink1(-/-) zebrafish are the first vertebrate model of PINK1 deficiency with loss of dopaminergic neurons. Our study also identifies TIGAR as a promising novel target for disease-modifying therapy in PINK1-related PD. Ann Neurol 2013;74:837-847
    Annals of Neurology 12/2013; 74(6). DOI:10.1002/ana.23999
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    ABSTRACT: Background. Haptic robots allow the exploitation of known motor learning mechanisms, representing a valuable option for motor treatment after stroke. The aim of this feasibility multicentre study was to test the clinical efficacy of a haptic prototype, for the recovery of hand function after stroke. Methods. A prospective pilot clinical trial was planned on 15 consecutive patients enrolled in 3 rehabilitation centre in Italy. All the framework features of the haptic robot (e.g., control loop, external communication, and graphic rendering for virtual reality) were implemented into a real-time MATLAB/Simulink environment, controlling a five-bar linkage able to provide forces up to 20 [N] at the end effector, used for finger and hand rehabilitation therapies. Clinical (i.e., Fugl-Meyer upper extremity scale; nine hold pegboard test) and kinematics (i.e., time; velocity; jerk metric; normalized jerk of standard movements) outcomes were assessed before and after treatment to detect changes in patients' motor performance. Reorganization of cortical activation was detected in one patient by fMRI. Results and Conclusions. All patients showed significant improvements in both clinical and kinematic outcomes. Additionally, fMRI results suggest that the proposed approach may promote a better cortical activation in the brain.
    Computational and Mathematical Methods in Medicine 11/2013; 2013:895492. DOI:10.1155/2013/895492
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    ABSTRACT: MicroRNAs (miRNAs) are small, abundant RNA molecules that constitute part of the cell's non-coding RNA "dark matter." In recent years, the discovery of miRNAs has revolutionised the traditional view of gene expression and our understanding of miRNA biogenesis and function has expanded. Altered expression of miRNAs is increasingly recognized as a feature of many disease states, including neurodegeneration. Here, we review the emerging role for miRNA dysfunction in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and Huntington's disease pathogenesis. We emphasize the complex nature of gene regulatory networks and the need for systematic studies, with larger sample cohorts than have so far been reported, to reveal the most important miRNA regulators in disease. Finally, miRNA diversity and their potential to target multiple pathways, offers novel clinical applications for miRNAs as biomarkers and therapeutic agents in neurodegenerative diseases.
    Frontiers in Cellular Neuroscience 10/2013; 7:178. DOI:10.3389/fncel.2013.00178
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    ABSTRACT: Discovery of intronic hexanucleotide repeat expansions of the C9ORF72 gene in a significant proportion of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)(1,2) was an important step for research into these disorders. The C9ORF72 genetic variant is more common than other described mutations and, unlike patients with mutations in SOD1, C9ORF72-ALS clinically and pathologically resembles the more numerous sporadic form.(3) However, progress has been limited by lack of understanding of the function of the C9ORF72 locus in health and disease. It is unknown whether the expansion causes disease by a gain of toxicity, or whether it disrupts expression of the wild-type protein encoded by the C9ORF72 gene, or some combination of both mechanisms.(1,2,4.)
    Neurology 10/2013; DOI:10.1212/01.wnl.0000435295.41974.2e
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    ABSTRACT: Stress is one of the most frequently self-identified seizure triggers in patients with epilepsy; however, most previous publications on stress and epilepsy have focused on the role of stress in the initial development of epilepsy. This narrative review explores the causal role of stress in triggering seizures in patients with existing epilepsy. Findings from human studies of psychological stress, as well as of physiologic stress responses in humans and animals, and evidence from nonpharmacologic interventions for epilepsy are considered. The evidence from human studies for stress as a trigger of epileptic seizures is inconclusive. Although retrospective self-report studies show that stress is the most common patient-perceived seizure precipitant, prospective studies have yielded mixed results and studies of life events suggest that stressful experiences only trigger seizures in certain individuals. There is limited evidence suggesting that autonomic arousal can precede seizures. Interventions designed to improve coping with stress reduce seizures in some individuals. Studies of physiologic stress using animal epilepsy models provide more convincing evidence. Exposure to exogenous and endogenous stress mediators has been found to increase epileptic activity in the brain and trigger overt seizures, especially after repeated exposure. In conclusion, stress is likely to exacerbate the susceptibility to epileptic seizures in a subgroup of individuals with epilepsy and may play a role in triggering "spontaneous" seizures. However, there is currently no strong evidence for a close link between stress and seizures in the majority of people with epilepsy, although animal research suggests that such links are likely. Further research is needed into the relationship between stress and seizures and into interventions designed to reduce perceived stress and improve quality of life with epilepsy.
    Epilepsia 10/2013; 54(11). DOI:10.1111/epi.12377
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    ABSTRACT: Ribosome-inactivating proteins (RIPs) were first isolated over a century ago and have been shown to be catalytic toxins that irreversibly inactivate protein synthesis. Elucidation of atomic structures and molecular mechanism has revealed these proteins to be a diverse group subdivided into two classes. RIPs have been shown to exhibit RNA N-glycosidase activity and depurinate the 28S rRNA of the eukaryotic 60S ribosomal subunit. In this review, we compare archetypal RIP family members with other potent toxins that abolish protein synthesis: the fungal ribotoxins which directly cleave the 28S rRNA and the newly discovered Burkholderia lethal factor 1 (BLF1). BLF1 presents additional challenges to the current classification system since, like the ribotoxins, it does not possess RNA N-glycosidase activity but does irreversibly inactivate ribosomes. We further discuss whether the RIP classification should be broadened to include toxins achieving irreversible ribosome inactivation with similar turnovers to RIPs, but through different enzymatic mechanisms.
    Virulence 09/2013; 4(8). DOI:10.4161/viru.26399
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    ABSTRACT: Predictive coding frameworks of perception propose that neural networks form predictions of expected input and generate prediction errors when the external input does not match expectation. We therefore investigated the processing of unexpected sounds and silence in the auditory cortex using fMRI. Unexpected sounds, when compared to expected sounds, evoked greater activation in large areas of the left temporal and insular cortices. Additionally the left middle temporal gyrus exhibited greater activation to unexpected events in general, whether sounds or silence, when compared to the corresponding expected events. These findings support predictive coding models of perception, which suggest that regions of the temporal cortex function to integrate sensory information with predictive signals during auditory perception.
    Neuropsychologia 08/2013; DOI:10.1016/j.neuropsychologia.2013.07.019
  • Journal of Neurology 07/2013; DOI:10.1007/s00415-013-7027-7
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    ABSTRACT: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. Substantial evidence implicates oxidative stress and mitochondrial dysfunction as early events in disease progression. Our aim was to ascertain whether mutation of the SOD1 protein increases metabolic functional susceptibility to oxidative stress. Here we used a motor neuron-like cell line (NSC34) stably transfected with various human mutant SOD1 transgenes (G93A, G37R, H48Q) to investigate the impact of oxidative stress on cell viability and metabolic function within intact cells. NSC34 cells expressing mutant SOD1 showed a dose dependent reduction in cell viability when exposed to oxidative stress induced by hydrogen peroxide, with variation between mutations. The G93A transfectants showed greater cell death and LDH release compared to cells transfected with the other SOD1 mutations, and H48Q showed an accelerated decline at later time points. Differences in mitochondrial bioenergetics, including mitochondrial respiration, coupling efficiency and proton leak, were identified between the mutations, consistent with the differences observed in viability. NSC34 cells expressing G93A SOD1 displayed reduced coupled respiration and mitochondrial membrane potential compared to controls. Furthermore, the G93A mutation had significantly increased metabolic susceptibility to oxidative stress, with hydrogen peroxide increasing ROS production, reducing both cellular oxygen consumption and glycolytic flux in the cell. This study highlights bioenergetic defects within a cellular model of ALS and suggests that oxidative stress is not only detrimental to oxygen consumption but also glycolytic flux, which could lead to an energy deficit in the cell.
    PLoS ONE 06/2013; 8(6):e68256. DOI:10.1371/journal.pone.0068256
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