Amyotrophic lateral sclerosis--a model of corticofugal axonal spread

Abstract

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.

Figure 1

Sequential progression of pTDP-43 pathology in amyotrophic lateral sclerosis. Stage 1: lesions develop in the agranular neocortex and bulbar (XII)/spinal somatomotor neurons. Stage 2: pathology occurs in the reticular formation, precerebellar nuclei, and portions of the thalamus. Aggregates develop in the parvocellular portion of the RN and pars compacta of the SN. Stage 3: the postcentral neocortex and striatum (CN and PU) develop lesions. Stage 4: TE and EN regions, hippocampal area CA1–2 and dentate fascia become involved. Abbreviations: CN, caudate nucleus; EN, entorhinal region; LT, lateral thalamus; MD, medial thalamus; PU, putamen; pTDP-43, phosphorylated 43 kDa transactive response DNA-binding protein; RN, red nucleus; SN, substantia nigra; TE, transentorhinal region.

Figure 2

Corticofugal connections between regions of involvement in amyotrophic lateral sclerosis. Colour intensity indicates the dissemination of pathology during successive neuropathological stages of disease. Grey indicates regions that are not involved. The colour-coded arrows show corticofugal pathways along which the disease process could disseminate, thereby spreading lesions within these relays. Abbreviations: enc, encephalin-containing neurons; sub P, substance P-containing neurons.

Figure 3

Putative mechanism of pTDP-43 propagation from cortical to subcortical neuronal projections. Initially, soluble pTDP-43 in the somatodendritic compartment of large motor cortex neurons is rapidly converted into dash-like or skein-like aggregates (black), but remains soluble (red) in axons. Intra-axonal soluble pTDP-43 might induce secondary lesions in topographically distant nerve cells that are innervated by these pTDP-43-propagating axons. Discontinuities within axons indicate that they are depicted in an artificially shortened form. Abbreviation: pTDP-43, phosphorylated 43 kDa transactive response DNA-binding protein.