Absence of subcerebral projection neurons delays disease onset and extends survival in a mouse model of ALS release_rev_98cd051f-1656-46a3-99e2-e019e4eba561

by Thibaut Burg, Charlotte Bichara, Jelena Scekic-Zahirovic, Mathieu Fischer, Geoffrey Stuart-Lopez, François Lefebvre, Matilde Cordero-Erausquin, Caroline Rouaux

Released as a post by Cold Spring Harbor Laboratory.

2019  

Abstract

<jats:title>Abstract</jats:title>Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease of adulthood that affects voluntary motricity and rapidly leads to full paralysis and death. ALS arises from the combined degeneration of motoneurons in the spinal cord and brain stem, responsible for muscle denervation, and corticospinal projection neurons (CSN), responsible for emergence of the upper motor neuron syndrome. Recent studies carried on ALS patients suggest that the disease may initiate in the motor cortex and spread to its projection targets. However, this "corticofugal hypothesis" of ALS has not yet been specifically challenged. Here, we provide a direct test of this hypothesis by genetically removing subcerebral projection neurons (SubCerPN), including CSN, in <jats:italic>Sod1<jats:sup>G86R</jats:sup></jats:italic> mice, a mouse model of ALS. Ablation of the transcription factor <jats:italic>Fezf2</jats:italic>, leading to the complete absence of all SubCerPN, delays disease onset, reduces weight loss and motor impairment, and increases survival without modifying disease duration. Importantly absence of SubCerPN and CSN also limits pre-symptomatic hyperreflexia. Together, our results demonstrate that major corticofugal tracts are critical to ALS onset, and that SubCerPN and CSN in particular may carry detrimental signals to their downstream targets. In its whole, this study provides first experimental arguments in favour of the corticofugal hypothesis of ALS.
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Date   2019-11-21
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