Abstract
The motor neuron disease amyotrophic lateral sclerosis (ALS) is a devastating condition with limited treatment options. The past few years have witnessed a ramping up of translational ALS research, offering the prospect of disease-modifying therapies. Although breakthroughs using gene-targeted approaches have shown potential to treat patients with specific disease-causing mutations, the applicability of such therapies remains restricted to a minority of individuals. Therapies targeting more general mechanisms that underlie motor neuron pathology in ALS are therefore of considerable interest. ALS pathology is associated with disruption to a complex array of key cellular pathways, including RNA processing, proteostasis, metabolism and inflammation. This Review details attempts to restore cellular homeostasis by targeting these pathways in order to develop effective, broadly-applicable ALS therapeutics.
Key points
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Amyotrophic lateral sclerosis (ALS) is a complex clinico-pathological syndrome with multiple pathways contributing to disease pathogenesis that are potentially suitable for therapeutic targeting.
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RNA-binding protein mislocalisation results in changes to RNA splicing, particularly cryptic exon inclusion, which can be therapeutically targeted by antisense oligonucleotides.
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Improving protein homeostasis, from folding to transport to degradation, can decrease protein aggregates.
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Boosting cellular bioenergetics can support neuronal health by correcting dysregulation of metabolic pathways, including mitochondrial dysfunction.
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Targeting neuronal and/or systemic inflammation has the potential to confer neuroprotection.
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A combination of therapies is likely to be required to address ALS pathogenesis using a personalized medicine approach.
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Acknowledgements
The authors thank the funders for their support. K.M.E.F. is supported by an Academy of Medical Sciences Starter Grant for Clinical Lecturers and a Medical Research Council Clinician Scientist Fellowship/Motor Neurone Disease Association Lady Edith Wolfson Clinical Fellowship. H.C. is funded by a LifeArc pathfinder grant. T.H.G. acknowledges funding support relevant to the topic of this Review from Motor Neuron Disease Scotland, My Name’5 Doddie Foundation and LifeArc.
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T.H.G. has provided advisory services to Novartis and Roche and serves on motor neuron disease advisory boards for LifeArc.
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Faller, K.M.E., Chaytow, H. & Gillingwater, T.H. Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis. Nat Rev Neurol 21, 86–102 (2025). https://doi.org/10.1038/s41582-024-01049-4
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DOI: https://doi.org/10.1038/s41582-024-01049-4
