Absence of Subcerebral Projection Neurons Is Beneficial in a Mouse Model of Amyotrophic Lateral Sclerosis

Abstract

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: Sod1 G86R 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.

Orbitofrontal-hypothalamic projections are disrupted in hypermetabolic murine ALS model and human patients

“…Alternatively, it is possible that any pathogenic event in motor cortex (propagating prionoids or abnormal activity patterns) may propagate to hypothalamus and drive its dysfunction and degeneration (as suggested for spinal cord [67]).…”

“…It is conceivable that LHA may receive inputs relaying the average motor activity performed or planned and may adjust energy balance accordingly; disruption of connectivity between motor cortex and hypothalamus may leave the latter “free running”, without a proper estimate of current motor activity. Alternatively, it is possible that any pathogenic event in motor cortex (propagating prionoids or abnormal activity patterns) may propagate to hypothalamus and drive its dysfunction and degeneration (as suggested for spinal cord [67]).…”

Upper and Lower Motor Neuron Degenerations Are Somatotopically Related and Temporally Ordered in the Sod1 Mouse Model of Amyotrophic Lateral Sclerosis

“…The L1–L4 lumbar level of the spinal cords were cut on a vibratome into coronal sections of 40 μm. Four nonadjacent sections spaced by 320 μm were labelled by immunohistochemistry as previously described [ 25 ], using a goat anti-choline acetyltransferase (ChAT) antibody (Millipore, Burlington, MA, USA) and a biotinylated donkey anti-goat IgG (Jackson ImmunoResearch, West Grove, PA, USA). Two images per section (one per ventral horn) were captured using an AxioImager.…”

“…Tibialis anterior muscles were dissected into bundles and processed for immunofluorescence with a rabbit anti-synaptophysin antibody and a rabbit anti-neurofilament antibody (Eurogentec, Seraing, Belgium) followed by Alexa-conjugated donkey anti-rabbit (Jackson) and rhodamine-conjugated α-bungarotoxin (Sigma), as previously described [ 25 ]. Neuromuscular junctions (NMJs) analysis was performed by an independent age and genotype-blinded observer, directly under and AxioImager.…”

Amyotrophic Lateral Sclerosis: Fuel for the Corticofugal Feud

“…Burg et al have tested the corticofugal hypothesis in ALS mice bearing the SOD1 G86R transgene by examining disease progression when CMNs are genetically ablated by eliminating the gene for the zinc‐finger transcription factor Fezf2; these mice lack layer V cortical projection neurons (SubCerPN), as well as neurons in the superior colliculus, brainstem, and hypothalamus 2 . Deletion of these neurons improved survival in Fezf2 knockout/SOD1 G86R (KO/SOD1 G86R ) mice by more than 20% compared with SOD1 G86R mice and induced a long‐lasting arrest of weight loss in the KO/ SOD1 G86R mice.…”