Amyotrophic Lateral Sclerosis as a Pseudo-Prion Disorder of Axonal Infrastructure

This manuscript proposes a mechanistic framework for sporadic amyotrophic lateral sclerosis (ALS), framing the disease as a pseudo-prion–like disorder of axonal infrastructure rather than a primary proteinopathy. The model integrates focal onset, network-based propagation, prolonged prodromal phase, distal axon dysfunction (“dying back”), threshold collapse, and secondary TDP-43 pathology into a unified upstream failure mode centered on progressive destabilization of axonal architecture, impaired local translation, and loss of regional proteome renewal. The framework reconciles sporadic and familial ALS via convergent downstream mechanisms and generates experimentally testable predictions, particularly in compartmentalized iPSC-derived motor neuron systems.