Neuronal and axonal degeneration in multiple sclerosis (MS) is a slow process initiated by acute lymphocytic inflammation, and subsequently driven by chronically smouldering, diffuse parenchymal myeloid and meningeal lymphocytic inflammation
Oxidative stress, mitochondrial injury and subsequent ion channel dysfunction secondary to chronic inflammation seem to have a constant impact on neurons and axons, leading to their demise during progressive MS
Several ion channels show compensatory changes in response to the inflammatory stimulus by altering their relative distribution in the neuron—a process that eventually becomes maladaptive and perpetuates neuroaxonal injury
Several neuroprotective pathways have been identified in MS, but these pathways become overridden, resulting in neuronal degeneration that is probably mediated by the initiation of apoptosis and Wallerian degeneration
The balance between continuous inflammatory stressors and intrinsic buffering mechanisms depends partly on age, sex and genetic factors, which eventually determine the clinical course of MS
In an animal model of MS, few molecular targets with proven neuroprotective properties that are separable from their impact on inflammatory responses have been identified; these molecules include CyPD, ASIC1 and TRPM4
Multiple sclerosis (MS) is the most frequent chronic inflammatory disease of the CNS, and imposes major burdens on young lives. Great progress has been made in understanding and moderating the acute inflammatory components of MS, but the pathophysiological mechanisms of the concomitant neurodegeneration—which causes irreversible disability—are still not understood. Chronic inflammatory processes that continuously disturb neuroaxonal homeostasis drive neurodegeneration, so the clinical outcome probably depends on the balance of stressor load (inflammation) and any remaining capacity for neuronal self-protection. Hence, suitable drugs that promote the latter state are sorely needed. With the aim of identifying potential novel therapeutic targets in MS, we review research on the pathological mechanisms of neuroaxonal dysfunction and injury, such as altered ion channel activity, and the endogenous neuroprotective pathways that counteract oxidative stress and mitochondrial dysfunction. We focus on mechanisms inherent to neurons and their axons, which are separable from those acting on inflammatory responses and might, therefore, represent bona fide neuroprotective drug targets with the capability to halt MS progression.
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M.A.F. is supported by the Deutsche Forschungsgemeinschaft Emmy Noether-Programme (FR1720/3-1), Gemeinnützige Hertie-Stiftung (1.01.1/11/003 and P1130075), Werner Otto Stiftung (1/81), Forschungs- und Wissenschaftsstiftung Hamburg, Boehringer Ingelheim Stiftung Exploration Grant and BMBF Biopharma (NEU2 programme). L.F. is supported by the Wellcome Trust, the Medical Research Council, the Lundbeck Foundation and the Naomi Bransom Foundation.
The authors declare no competing financial interests.
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Friese, M., Schattling, B. & Fugger, L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Rev Neurol 10, 225–238 (2014). https://doi.org/10.1038/nrneurol.2014.37
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