Amyotrophic lateral sclerosis—a model of corticofugal axonal spread

Prion-like propagation of pathogenic proteins has been suggested to underlie several neurodegenerative diseases. In this Perspectives article, Braak et al. posit that progressive lesions in amyotrophic lateral sclerosis (ALS) spread through cell-to-cell transfer of 43-kDA transactive response DNA-binding protein, mainly through cortical neuronal projections to other brain areas and the spinal cord. This model could have important implications for our understanding of ALS and approach to treatment. 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.