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Objective Recent studies carried out on amyotrophic lateral sclerosis patients suggest that the disease might initiate in the motor cortex and spread to its targets along the corticofugal tracts. In this study, we aimed to test the corticofugal hypothesis of amyotrophic lateral sclerosis experimentally. Methods Sod1G86R and Fezf2 knockout mouse lines were crossed to generate a model that expresses a mutant of the murine Sod1 gene ubiquitously, a condition sufficient to induce progressive motor symptoms and premature death, but genetically lacks corticospinal neurons and other subcerebral projection neurons, one of the main populations of corticofugal neurons. Disease onset and survival were recorded, and weight and motor behavior were followed longitudinally. Hyper-reflexia and spasticity were monitored using electromyographic recordings. Neurodegeneration and gliosis were assessed by histological techniques. Results Absence of subcerebral projection neurons delayed disease onset, reduced weight loss and motor impairment, and increased survival without modifying disease duration. Absence of corticospinal neurons also limited presymptomatic hyper-reflexia, a typical component of the upper motoneuron syndrome. Interpretation Major corticofugal tracts are crucial to the onset and progression of amyotrophic lateral sclerosis. In the context of the disease, subcerebral projection neurons might carry detrimental signals to their downstream targets. In its entirety, this study provides the first experimental arguments in favor of the corticofugal hypothesis of amyotrophic lateral sclerosis. journal article research support, non-u.s. gov't 2020 10 2020 07 11 imported

International audience; Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects selected cortical and spinal neuronal populations, leading to progressive paralysis and death. A growing body of evidences suggests that the disease may originate in the cerebral cortex and propagate in a corticofugal manner. In particular, transcranial magnetic stimulation studies revealed that ALS patients present with early cortical hyperexcitability arising from a combination of increased excitability and decreased inhibition. Here, we discuss the possibility that initial cortical circuit dysfunction might act as the main driver of ALS onset and progression, and review recent functional, imaging and transcriptomic studies conducted on ALS patients, along with electrophysiological, pathological and transcriptomic studies on animal and cellular models of the disease, in order to evaluate the potential cellular and molecular origins of cortical hyperexcitability in ALS.

Amyotrophic lateral sclerosis (ALS) arises from the combined degeneration of motor neurons (MN) and corticospinal neurons (CSN). Recent clinical and pathological studies suggest that ALS might start in the motor cortex and spread along the corticofugal axonal projections (including the CSN), either via altered cortical excitability and activity or via prion-like propagation of misfolded proteins. Using mouse genetics, we recently provided the first experimental arguments in favour of the corticofugal hypothesis, but the mechanism of propagation remained an open question. To gain insight into this matter, we tested here the possibility that the toxicity of the corticofugal projection neurons (CFuPN) to their targets could be mediated by their cell autonomous-expression of an ALS causing transgene and possible diffusion of toxic misfolded proteins to their spinal targets. We generated a Crym-CreERT2 mouse line to ablate the SOD1G37R transgene selectively in CFuPN. This was sufficient to fully rescue the CSN and to limit spasticity, but had no effect on the burden of misfolded SOD1 protein in the spinal cord, MN survival, disease onset and progression. The data thus indicate that in ALS corticofugal propagation is likely not mediated by prion-like mechanisms, but could possibly rather rely on cortical hyperexcitability. ispartof: PROGRESS IN NEUROBIOLOGY vol:200 ispartof: location:England status: published