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OBJECTIVE: Recent studies carried on amyotrophic lateral sclerosis patients suggest that the disease may initiate in the motor cortex and spread to its targets along the corticofugal tracts. In this study, we aimed at experimentally testing the corticofugal hypothesis of amyotrophic lateral sclerosis. METHODS: Sod1G86R and Fezf2 knockout mouse lines were crossed to generate a model that ubiquitously expresses a mutant of the murine Sod1 gene, 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 behaviour were longitudinally followed. Hyperreflexia and spasticity were monitored using electromyographic recordings. Neurodegeneration and gliosis were further 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 pre-symptomatic hyperreflexia, a typical component of the upper motor neuron syndrome. INTERPRETATION: Major corticofugal tracts are critical to amyotrophic lateral sclerosis onset and progression. In the context of the disease, subcerebral projection neurons may carry detrimental signals to their downstream targets. In its whole, this study provides the first experimental arguments in favour of the corticofugal hypothesis of amyotrophic lateral sclerosis. This article is protected by copyright. All rights reserved.

Original publication

DOI

10.1002/ana.25833

Type

Journal article

Journal

Ann Neurol

Publication Date

26/06/2020