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Is autoimmunity in multiple sclerosis secondary to neurodegeneration?
Albert HC Wong, Fang Liu
Journal of Translational Neuroscience. 2016, 1 (2): 49-55.
https://doi.org/10-3868/j.issn.2096-0689.2016.02.004
Abstract Multiple sclerosis (MS) is characterized by neurological symptoms that are separated in time and space, which correlate with demyelination and white matter lesions. The conventional pathophysiological model is that an autoimmune reaction against the myelinated nerve sheath results in demyelination, accompanied by axon damage and the death of oligodendrocytes that produce myelin. There is no cure for MS, but current treatments are primarily aimed at suppressing the autoimmune reaction, with the goal of reducing demyelination.
These treatments have limited efficacy and developing better treatments for MS remains an important goal. Here we argue that the autoimmune reaction may be secondary to neurodegeneration or neurotoxicity, and that protecting neurons from glutamate-mediated toxicity may be a better therapeutic strategy than targeting the immune system. We have recently demonstrated that a protein-protein interaction between the GluR2 subunit of the AMPA (α-Amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid) glutamate receptor and GAPDH (Glyceraldehyde 3-phosphate dehydrogenase) is elevated in human MS plaques and in an animal model of MS. Disrupting this interaction in a rodent model restores neurological function, preserves myelin, and protects
neurons, oligodendrocytes and axons. The peptide we created to block the GluR2-GAPDH interaction also reduces immune system activation, suggesting that autoimmunity is not necessarily the primary etiology in MS. The GluR2-GAPDH interaction may promote cell death via increased calcium influx through non-GluR2-containing AMPA receptors, or through the p53 and Siah1 cell death pathways.
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Optimising validity and translational potential in rodent models of brain disorders
Anthony J Hannan
Journal of Translational Neuroscience. 2016, 1 (2): 56-62.
https://doi.org/10-3868/j.issn.2096-0689.2016.02.005
Neurological and psychiatric disorders collectively constitute the greatest burden of disease. However, the human brain is the most complex of biological systems and therefore accurately modeling brain disorders presents enormous challenges. A large range of therapeutic approaches across a diverse collection of brain disorders have been found to show great promise in preclinical testing and then failed during clinical trials. There are a variety of potential reasons for such failures, on both the preclinical and clinical sides of the equation. In this article, I will focus on the key issues of validity in animal models. I will discuss two forms of construct validity, ‘genetic construct validity’ and ‘environmental construct validity’, which model specific aspects of the genome and ‘envirome’ relevant to the disorder in question. The generation of new gene-edited animal models has been facilitated by new technologies, the most notable of which are CRISPR-Cas systems. These and other technologies can be used to enhance construct validity. Finally, I will discuss how face validity can be optimized, via more sophisticated cognitive, affective and motor behavioural tests, translational tools and the integration of molecular, cellular and systems data. Predictive validity cannot yet be assessed for the many preclinical models where we currently lack effective clinical interventions, however this will change as the translational pipeline is honed to deliver therapies for a range of devastating disorders.
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