The prevailing motor neuron-centric view of amyotrophic lateral sclerosis (ALS) pathogenesis could be an important factor in the failure to identify disease-modifying therapy for this neurodegenerative disorder. Non-neuronal cells have crucial homeostatic functions within the CNS and evidence of involvement of these cells in the pathophysiology of several neurodegenerative disorders, including ALS, is accumulating. Microglia and astrocytes, in crosstalk with peripheral immune cells, can exert both neuroprotective and adverse effects, resulting in a highly nuanced range of neuronal and non-neuronal cell interactions. This Review provides an overview of the diverse roles of non-neuronal cells in relation to the pathogenesis of ALS and the emerging potential of non-neuronal cell biomarkers to advance therapeutic development.
Accumulating evidence suggests that an exclusively motor neuron-centred model of pathogenesis in amyotrophic lateral sclerosis (ALS) is untenable, with important implications for therapeutic development strategies.
Brain-resident microglia, astrocytes and oligodendrocytes as well as peripheral immune cells all have vital functions in CNS homeostasis and physiology.
In multiple experimental models of ALS, non-neuronal cells seem to exert neurotoxic effects via both gain-of-function and loss-of-function mechanisms but also apparently show neuroprotective activity at certain disease stages.
Many of the hypotheses surrounding the roles of non-neuronal cells in ALS pathogenesis were developed using rodent models, some of which have limited relevance to the TDP43 neuropathological hallmark of human ALS.
Human induced pluripotent stem cells permit the investigation of non-neuronal cells carrying ALS-associated genetic mutations, but multicellular co-cultures might be needed to disentangle their nuanced interactions with motor neurons.
Human biofluid biomarkers derived from non-neuronal cells offer an important window into the in vivo pathological milieu and show potential as early markers of therapeutic response.
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B. F. V. is funded by the University of Oxford Clarendon Fund, St John’s College Oxford, the Oxford–Medical Research Council (MRC) Doctoral Training Partnership, and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. E. G. is supported by the Motor Neurone Disease Association. A. G. T. is supported by the MRC and Motor Neurone Disease Association Lady Edith Wolfson Clinician Scientist Fellowship. S. A. C. is supported through the Oxford Martin School. M. R. T. is supported by the Motor Neurone Disease Association. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health and Social Care.
The authors declare no competing interests.
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Vahsen, B.F., Gray, E., Thompson, A.G. et al. Non-neuronal cells in amyotrophic lateral sclerosis — from pathogenesis to biomarkers. Nat Rev Neurol 17, 333–348 (2021). https://doi.org/10.1038/s41582-021-00487-8
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