Article Text

Download PDFPDF

How does ALS spread between neurones in the CNS?
  1. Michael Swash1,2
  1. 1Barts and the London School of Medicine, Queen Mary University of London, London, UK
  2. 2Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal
  1. Correspondence to Professor Michael Swash, mswash{at}

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

In recent years, the concept of contiguous spread of the disease process in amyotrophic lateral sclerosis (ALS) has become more accepted,1 although how this might occur is still uncertain. Kanouchi et al 2 reviewed the extensive clinical, physiological and molecular evidence for this process in this journal, noting that ALS can be recognised to spread both contiguously and non-contiguously, the latter implying more than one focus of disease onset—a ‘skipping’ pattern of spread. They concluded that contiguous spread explains regional progression, but offered no explanation for the process of propagation itself. It has been suggested that cell-to-cell spread requires that abnormal cytosolic proteins in ALS, for example, TDP-43, which seems to underlie the ubiquitinated inclusions so characteristic of sporadic ALS, are misfolded, self-aggregate and form toxic proteinaceous inclusions with a β cross-conformation, resembling prions.3 A prion-like propagation process implies that the abnormal protein spreads to involve other nearby cells, whether neuronal or glial. Prusiner,4 from whose insight the prion hypothesis was originally derived in understanding the pathogenesis of scrapie and Creutzfeldt–Jakob disease,5 has suggested that this concept of propagation of misfolded cytosolic proteins is fundamental to the major neurodegenerative disorders.4 Thus, α synuclein in Parkinson's disease, TDP-43 in ALS, SOD-1 in one form of familial ALS and possibly also in sporadic ALS, τ protein in fronto-temporal dementia, and A-beta amyloid plaques in Alzheimer dementia are all characterised by insoluble proteinaceous intracellular inclusions in the brain that have been described as ‘prion-like’.5 A similar process has been suggested to occur in Huntington's disease.4 These disorders all show a relatively orderly progression from their different sites of origin in the brain to a more widespread pathology as the disease advances,4 ,6 ,7 although a multicentric origin has also been suggested in ALS.

Contiguous disease spread requires a mechanism for cell-to-cell transmission of insoluble misfolded protein. There are a number of possibilities, for example, transynaptic transmission, transmission through membrane channels or a mechanism involving glial cell intrusions into neurones,8 but these lack convincing biological evidence in ALS itself. A more likely mechanism, attributable to both glial cells and to neurones, as well as to microglia, is phagocytosis, or endocytosis of extracellular proteinaceous material. Phagocytosis is defined as the cellular ingestion of particulates greater than 0.5 μm diameter; endocytosis involves ingestion of smaller particles.9 Phagocytosis—of extracellular material—is a property of neurones,10 as it is of other cell types, such as macrophages.9 Bowen et al 10 in both in vitro and in vivo experiments showed that different neuronal types can phagocytose cell debris and synthetic particles as large as 2.8 μm diameter and that this ingested material can be transported from distal dendrites into the cell body, where it may persist. There is evidence that this phagocytic capacity is determined by certain classes of integrin receptors known to be present on neurones. This process might, indeed, both account for neuronal inclusions and for cell-to-cell spread in prion and prion-like disorders, such as ALS, including the latter's characteristic regional spread within the motor system. Misfolded proteins released into the extracellular space from dying cells during apoptotic or autolytic cell death or following their release by exocytosis might therefore ‘infect’ healthy neighbouring neural cells through endocytotic or phagocytic ingestion.4 ,9 ,10 Phagocytosis, endocytosis and related processes use different cellular mechanisms in the ingestion of extracellular material.9 ,10 In contrast to these processes, autophagy is essential in the degradation and removal of abnormal damaged protein from the cell. This process involves the ubiquitin proteasome system, and is important in the maintenance of cell structure and function not only in the cell soma but in dendrites, axons and synapses.11 Disruption of these processes has been implicated as a general feature in the pathogenesis of neurodegenerative disorders.12

In ALS all motor neurone types in the cord are affected, including anterior horn cells, γ motor neurones and interneurons. In the cerebrum, there is neuronal loss in the primary and premotor cortex, in the frontal lobes and more widely in basal ganglia. The neurones of Clarke's nucleus, and thalamic neurones, are also affected. The disease therefore spreads beyond the traditional limits of the motor system, although the disease is always an anteriorly predominant brain degeneration, sparing primary sensory systems and the occipito-parietal cortex. The factors determining this susceptibility are not understood, but imply properties specific to motor cells or their connexions, just as the specific patterns of spread of Parkinson's disease and Alzheimer's disease imply inherently determined neuronal susceptibility in these disorders.

If neuronal phagocytosis or endocytosis is important in cell-to-cell transmission of misfolded prion-like protein in ALS,4 ,10–12 and indeed in other neurodegenerative disorders, this may offer an important window into therapy in the early stages of the disease.



  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.