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

Anastasya Birger,Oded Behar,Benjamin Reubinoff,Miri Ottolenghi,Liat Perez

doi:10.1038/s41419-018-0294-6

Anastasya Birger, Oded Behar + Show 3 more

Open Access

https://doi.org/10.1038/s41419-018-0294-6

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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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a late-onset, progressive and fatal neurodegenerative disease that affects both cortical and spinal cord motor neurons (MNs)[1]
In contrast to its effects on other neurons tested so far, it seems that Semaphorin 3A (Sema3A) functions as a survival factor for mouse spinal motor neurons, since deletion of this gene only in astrocytes results in Official journal of the Cell Death Differentiation Association
Hb9-GFP-human embryonic stem cell (hESC) were differentiated into MNs as described in Fig. 1a and the “Methods” section

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a late-onset, progressive and fatal neurodegenerative disease that affects both cortical (upper) and spinal cord (lower) motor neurons (MNs)[1]. One strategy to decipher the molecular mechanisms affecting motor neuron loss in ALS is by looking for factors with positive or negative functional roles during motor neuron development. One such example is the guidance molecule Semaphorin 3A (Sema3A). Sema3A is a member of a family of proteins, best known to function as axon chemo-repellents during development of various cells including spinal MNs3. In contrast to its effects on other neurons tested so far, it seems that Sema3A functions as a survival factor for mouse spinal motor neurons, since deletion of this gene only in astrocytes results in Official journal of the Cell Death Differentiation Association

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