Amyotrophic lateral sclerosis--a model of corticofugal axonal spread

Nat Rev Neurol. 2013 Dec;9(12):708-14. doi: 10.1038/nrneurol.2013.221. Epub 2013 Nov 12.


The pathological process underlying amyotrophic lateral sclerosis (ALS) is associated with the formation of cytoplasmic inclusions consisting mainly of phosphorylated 43-kDa transactive response DNA-binding protein (pTDP-43), which plays an essential part in the pathogenesis of ALS. Preliminary evidence indicates that neuronal involvement progresses at different rates, but in a similar sequence, in different patients with ALS. This observation supports the emerging concept of prion-like propagation of abnormal proteins in noninfectious neurodegenerative diseases. Although the distance between involved regions is often considerable, the affected neurons are connected by axonal projections, indicating that physical contacts between nerve cells along axons are important for dissemination of ALS pathology. This article posits that the trajectory of the spreading pattern is consistent with the induction and dissemination of pTDP-43 pathology chiefly from cortical neuronal projections, via axonal transport, through synaptic contacts to the spinal cord and other regions of the brain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • Axonal Transport / physiology*
  • Axons / physiology
  • Cerebral Cortex / metabolism*
  • Cerebral Cortex / pathology
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Models, Neurological*
  • Synaptic Transmission / physiology*


  • DNA-Binding Proteins