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Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a genetically diverse disease. At least 15 ALS-associated gene loci have so far been identified, and the causative gene is known in approximately 30% of familial ALS cases. Less is known about the factors underlying the sporadic form of the disease. The molecular mechanisms of motor neuron degeneration are best understood in the subtype of disease caused by mutations in superoxide dismutase 1, with a current consensus that motor neuron injury is caused by a complex interplay between multiple pathogenic processes. A key recent finding is that mutated TAR DNA-binding protein 43 is a major constituent of the ubiquitinated protein inclusions in ALS, providing a possible link between the genetic mutation and the cellular pathology. New insights have also indicated the importance of dysregulated glial cell–motor neuron crosstalk, and have highlighted the vulnerability of the distal axonal compartment early in the disease course. In addition, recent studies have suggested that disordered RNA processing is likely to represent a major contributing factor to motor neuron disease. Ongoing research on the cellular pathways highlighted in this Review is predicted to open the door to new therapeutic interventions to slow disease progression in ALS.

Key Points

  • Multiple cellular events contribute to the pathobiology of amyotrophic lateral sclerosis (ALS), including oxidative stress, mitochondrial dysfunction, excitotoxicity, protein aggregation, impaired axonal transport, neuroinflammation, and dysregulated RNA signaling

  • TAR DNA-binding protein 43 is a major constituent of the ubiquitinated protein inclusions found in surviving motor neurons in most forms of ALS

  • Glial pathology and disruption of glial cell–motor neuron communication contribute to neurodegeneration and the propagation of motor neuron injury

  • Understanding the links between molecular changes and clinical features of the disease should guide future therapeutic efforts

  • Degenerative changes in motor neurons seem to affect the health of the distal axonal compartment at an early stage of disease, highlighting an important neuroprotective target

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Figure 1: Molecular mechanisms of motor neuron injury in ALS.
Figure 2: Mitochondrial dysfunction in ALS.
Figure 3: Emerging evidence for dysregulation of RNA processing in ALS.

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Acknowledgements

The authors gratefully acknowledge financial support provided by the Wellcome Trust, the UK Motor Neurone Disease Association, the Medical Research Council, The Hermann und Lilli Schilling Stiftung, the Deutsche Forschungsgemeinschaft, the European Union under the 7th Framework Programme for RTD—Project MitoTarget (Grant Agreement HEALTH-F2-2008-223388), Project EuroMotor (Grant Agreement FP7/2007-2013 259867), and the ALS Association.

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Ferraiuolo, L., Kirby, J., Grierson, A. et al. Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis. Nat Rev Neurol 7, 616–630 (2011). https://doi.org/10.1038/nrneurol.2011.152

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