Threshold Model of Axonal Infrastructure Collapse in ALS: Pseudo-Prion Dynamics, Energetics, and Phenotypic Spectrum

In a previous work (Gorzelnik, 2026) it was proposed that the sporadic form of amyotrophic lateral sclerosis (ALS) may begin with a rare conformational destabilization of large architectural proteins of the axon (spectraplakin/MACF1), leading to pseudo-prion degradation of the cytoskeletal infrastructure and secondary TDP-43 pathology. Here we formalize and expand this conceptual framework. We specify the role of spectraplakins as unloading nodes of local translation and demonstrate that their loss leads to toxic overload of synaptic terminals—reversing the classical dying-back logic. We introduce axonal caliber as a geometric variable determining selective vulnerability: the thick axons of alpha-motoneurons lack the diffusive redundancy available to the thin axons of gamma-motoneurons and oculomotor neurons. We formalize an autocatalytic energy–proteostatic loop and the concept of asynchronous proteome aging, explaining hyperexcitability and hypermetabolism as natural consequences of infrastructural collapse. We analyze upstream molecular aging as a factor lowering the initiation barrier, integrating sporadic and familial forms (C9orf72, SOD1, TARDBP/FUS) as variants of a single process. We identify the kinetic paradox of intra-axonal propagation as the central open problem of the model. We propose a unification of the ALS–FTD spectrum within a topological logic in which the clinical phenotype is a function of propagation geometry—tightly packed axonal bundles allow rapid transfer bypassing the proteolytic gate of the soma, whereas the dispersed architecture of the associative cortex filters and slows progression. The model generates falsifiable predictions including mapping of local translation, correlation of cytoskeletal disorganization with axonal caliber in presymptomatic models, and retrodictive explanations of environmental risk factors. The proposed framework integrates existing hypotheses of ALS pathogenesis as successive layers of a single infrastructural cascade.