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Expert
Reviews in Molecular Medicine: http://www.expertreviews.org/
Accession information: Vol. 8; Issue 11; 24 May 2006 Abstract
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Model to show how some of the proposed mechanisms in amyotrophic lateral sclerosis could interact to cause motor neuron degeneration
Emily F. Goodall and Karen E. Morrison
Figure 5. Model to show how some of the proposed mechanisms in amyotrophic lateral sclerosis could interact to cause motor neuron degeneration. Normal superoxide dismutase 1 (SOD1) functions as a detoxification enzyme, catalysing the conversion of superoxide ions to hydrogen peroxide, which is then converted to water by catalase and glutathione. Mutant SOD1, as seen in some familial amyotrophic lateral sclerosis (FALS) cases, may be toxic because it is unstable, forming aggregates in the motor neuron cytoplasm, axoplasm and mitochondria. These aggregates may interfere with normal proteasome function, and also with other cellular processes, such as neurofilament function, leading to impaired axonal transport and further toxic aggregation. Mutant SOD1 can also trigger oxidative reactions by various means including by increasing levels of peroxynitrite, which can then cause damage through the formation of hydroxyl radicals or via nitration of tyrosine residues on proteins. Mutant, but not normal, SOD1 has also been recently reported to be secreted extracellularly, from where it can trigger microglial activation. Oxidative stress impairs mitochondrial function and inhibits the function of EAAT2, the main glial glutamate transporter protein, responsible for most of the reuptake of synaptically released glutamate. Glutamate excess causes neurotoxicity by increasing intracellular calcium, which enhances oxidative stress and mitochondrial damage. Mitochondrial damage in turn leads to further oxidative stress, enhancing the pathogenic cascade. Microglial activation is seen in both familial and sporadic ALS. Inflammatory mediators released by activated microglia cause additional release of neuroinflammatory proteins from astocytes causing further inflammation and oxidative stress. Ultimately, neuronal cell death in ALS is thought to occur via a programmed cell-death pathway with features resembling apoptosis.
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