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Pathogenesis of two axonopathies does not require axonal neurofilaments

Abstract

Neurofilaments are a major component of the axonal cytoskeleton and their abnormal accumulation is a prominent feature of the cytopathology encountered in several neurodegenerative diseases1,2,3,4,5,6,7,8. Thus, an attractive and widely held model of pathogenesis involves the participation of disrupted neurofilaments as a common toxic intermediate9,10,11,12,13. Here, in direct contrast to this hypothesis, we show that two neurodegenerative disease models in the mouse, dystonia musculorum (dt)14,15 and a superoxide dismutase 1 (SOD1)-mediated form of human motor neuron disease (amyotrophic lateral sclerosis, ALS)16,17, progress with little or no abatement on a transgenic background in which neurofilaments are withheld from the axonal compartment18. By specifically excluding a necessary role for axonal neurofilaments, our observations redefine the components of the pathogenic pathway leading to axon disruption in these two degenerative diseases.

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Figure 1: Electron micrographs of typical axonal swellings in myelinated fibres in the spinal cord grey matter of dt/dt mice.
Figure 2: Cross-sections of dorsal roots from mice.
Figure 3: Axonal neurofilament deficiency does not prevent sensory axon degeneration in dt/dt mice.
Figure 4: Mitochondrial degeneration occurs in axons of SOD1 mutant mice, even in the absence of axonal neurofilaments.
Figure 5: Axonal sprouts arise in ventral roots of SOD1 mutant mice.

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Acknowledgements

We gratefully acknowledge the excellent technical assistance of T. Crossfield, K.Galloway-Kay, I. Tretjakoff and P. Valera. We also thank the ‘Centre de Microscopie Electronique de l'Université d'Angers’ and the Department of Neuropathology, MNI, for assistance in electron microscopy and image analysis. We are particularly grateful to J. Snipes, MNI, for helpful discussions. This investigation was supported through grants from the MRC and MDAC to A.C.P. and from the AFM to J.E. Travel support was provided by an INSERM/FRSQ award.

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Eyer, J., Cleveland, D., Wong, P. et al. Pathogenesis of two axonopathies does not require axonal neurofilaments. Nature 391, 584–587 (1998). https://doi.org/10.1038/35378

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