TARDBP and amyotrophic lateral sclerosis: Importantly, by assessing the extent of the TDP-43 pathology in other brain regions, the authors proposed a “corticofugal hypothesis of ALS,” with an origin of the pathology in the motor cortex, followed by a sequential corticofugal pattern of progression to the downstream targets of the motor cortex via a direct, mono-synaptic transmission, similar to a prion-like mechanism (Braak et al., 2013).