ALS-related human cortical and motor neurons survival is differentially affected by Sema3A

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by cell death of upper and lower motor neurons (MNs). The cause of MN cell loss is not completely understood but involves both cell autonomous and non-cell autonomous mechanisms. Numerous molecules have been implicated to be involved in the death of MNs. One such candidate is semaphorin 3A (Sema3A). In ALS patients, Sema3A was shown to be significantly upregulated in the motor cortex and downregulated in the spinal cord. In the mouse, Sema3A was shown to be an axon repellent molecule for MNs. Sema3A could also induce death of different neuronal types that are also repelled by it, including sensory, sympathetic, retinal, and cortical neurons. In contrast, astrocyte-specific knockout of Sema3A results in motor neuron cell death, consistent with the idea that Sema3A is a survival factor for mouse motor neurons. Here, we tested the response of human cortical neurons and spinal cord MNs to Sema3A. We found that Sema3A enhances the survival of spinal cord MNs. In contrast, Sema3A reduces the survival of cortical neurons. Thus, both upregulation of Sema3A in the cortex, or downregulation in the spinal cord of ALS patients is likely to directly contribute to MNs cell loss in ALS patients.

Increased Tau Phosphorylation in Motor Neurons From Clinically Pure Sporadic Amyotrophic Lateral Sclerosis Patients

“…Similarly the molecule semaphorin 3A, which has been implicated in the death of motor neurons, is increased in the motor cortex but reduced in the spinal cord of ALS patients, and has been shown to enhance survival of spinal cord motor neurons but reduce survival of cortical neurons [60]. Our data thus supports this different temporal progression of the mechanisms underlying disease progression in the upper versus lower motor neurons.…”

miR126-5p Downregulation Facilitates Axon Degeneration and NMJ Disruption via a Non–Cell-Autonomous Mechanism in ALS

“…Another explanation for this contradiction could be the fact that Sema3A plays a more complex role in the biology of MNs. Indeed, Sema3A was shown to increase survival when added to mass cultures of mouse MNs ( Molofsky et al, 2014 ) and human MNs ( Birger et al, 2018 ). Consistent with this, deletion of the Sema3A gene specifically in spinal astrocytes resulted in a gradual loss of spinal MNs ( Molofsky et al, 2014 ), thus suggesting that Sema3A has a positive effect when introduced near the cell body.…”

Functions of Plexins/Neuropilins and Their Ligands during Hippocampal Development and Neurodegeneration

“…Altered semaphorin function or expression is not confined exclusively to degenerative diseases related to the hippocampus. In fact, it is also well known that there is an association of certain semaphorins with other diseases, such as Sema4A with retinal degeneration [141], Sema3A-Np1 signaling with motor neuron degeneration [142,143], Sema3A, Sema7A, and Sema4D with multiple sclerosis [144,145], and Sema3A and Sema5A with Parkinson’s disease [146,147] (see also [47] for review).…”