Does Sporadic Amyotrophic Lateral Sclerosis Spread via Axonal Connectivities?

Abstract

Abstract The pathological process underlying sporadic amyotrophic lateral sclerosis (sALS) that is associated with the formation of cytoplasmic inclusions of a nuclear protein (TDP-43) is confined to only a few types of long-axoned projection neurons. The giant Betz pyramidal cells of the primary motor neocortex as well as large α-motor neurons of the lower brainstem and spinal cord become involved early. In the human brain, these 2 neuronal types are to a large extent interconnected by monosynaptic axonal projections. The cell nuclei of affected neurons gradually forfeit their normal expression of the protein TDP-43. In α-motor neurons, this nuclear loss is followed by the formation of insoluble TDP-43-immunopositive inclusions in the cytoplasm, whereas in Betz cells the loss of nuclear expression remains for an unknown period of time unaccompanied by somatodendritic and/or axoplasmic aggregations. It is possible that in cortical pyramidal cells (Betz cells) the nuclear clearing initially leads to the formation of an abnormal but still soluble cytoplasmic TDP-43 which may enter the axoplasm and, following transmission via direct synaptic contacts, induces anew TDP-43 dysregulation and aggregation in recipient neurons. The trajectory of the spreading pattern that consecutively develops during the course of sALS is consistent with the dissemination from chiefly cortical projection neurons via axonal transport through direct synaptic contacts leading to the secondary induction of TDP-43-containing inclusions within recipient nerve cells in involved subcortical regions.