There are no neuroprotective strategies to preserve the acutely demyelinated axon, highlighting a major and urgent unmet clinical need. In inflammatory demyelinating disorders such as MS, axons are damaged during acute demyelination, and they can also degenerate over much longer timescale due to chronic lack of myelin. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders.ĭemyelination leads to the damage and loss of axons and the progression of neurological disability in demyelinating disorders, including multiple sclerosis (MS).
Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons, and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochrome c oxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. However, the consequences of demyelination on neuronal and axonal biology are poorly understood. Enhanced axonal response of mitochondria to demyelination offers neuroprotection: implications for multiple sclerosisĪcta Neuropathologica volume 140, pages 143–167 ( 2020) Cite this articleĪxonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS).
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