Deciphering spreading mechanisms in amyotrophic lateral sclerosis: clinical evidence and potential molecular...

The aim of this review is to refer to recent arguments supporting the existence of specific propagation mechanisms associated with spreading of neuron injury in amyotrophic lateral sclerosis (ALS).

Misfolded ALS-linked protein accumulation can induce aggregation of their native equivalent isoforms through a mechanism analogous to the infectious prion proteins initiation and its propagation.

Although ALS is clinically heterogeneous, a shared characteristic is the focal onset and the progressive extension to all body regions. Being viewed until now as just summation of the increased number of affected neurons, dispersion is now rather considered as the result of a seeded self-propagating process. A sequential regional spreading pattern is supported by the distribution of TDP-43 aggregates in ALS autopsy cases. Electrophysiology and advanced neuroimaging methods also recently provided some evidence for propagation of lesions both in the brain and spinal cord, more longitudinal studies being still needed. Lesions are supposed to spread cell-to-cell regionally or through connected neuronal pathway. At the molecular level, the prion-like spreading is an emerging mechanism hypothesis, but other machineries such as those that are in charge of dealing with misfolded proteins and secretion of deleterious peptides may be involved in the propagation of neuron loss. Deciphering the mechanisms underlying spreading of ALS symptoms is of crucial importance to better understand this neurodegenerative disease, build new and appropriate animal models and to define novel therapeutic targets.