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

Christine Marques,Jelena Scekic-Zahirovic,Caroline Rouaux,Mathieu Fischer,Thibaut Burg

doi:10.3390/brainsci11030369

Christine Marques, Jelena Scekic-Zahirovic + Show 3 more

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https://doi.org/10.3390/brainsci11030369

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Journal: Brain sciences	Publication Date: Mar 13, 2021
Citations: 17	License type: CC BY 4.0

Affiliation: University of Strasbourg, Inserm

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disease arising from the combined degeneration of upper motor neurons (UMN) in the motor cortex, and lower motor neurons (LMN) in the brainstem and spinal cord. This dual impairment raises two major questions: (i) are the degenerations of these two neuronal populations somatotopically related? and if yes (ii), where does neurodegeneration start? If studies carried out on ALS patients clearly demonstrated the somatotopic relationship between UMN and LMN degenerations, their temporal relationship remained an unanswered question. In the present study, we took advantage of the well-described Sod1G86R model of ALS to interrogate the somatotopic and temporal relationships between UMN and LMN degenerations in ALS. Using retrograde labelling from the cervical or lumbar spinal cord of Sod1G86R mice and controls to identify UMN, along with electrophysiology and histology to assess LMN degeneration, we applied rigorous sampling, counting, and statistical analyses, and show that UMN and LMN degenerations are somatotopically related and that UMN depletion precedes LMN degeneration. Together, the data indicate that UMN degeneration is a particularly early and thus relevant event in ALS, in accordance with a possible cortical origin of the disease, and emphasize the need to further elucidate the molecular mechanisms behind UMN degeneration, towards new therapeutic avenues.

Highlights

Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease that mostly starts in adulthood and rapidly progresses to paralysis and death within only 2–5 years of diagnosis [1]
ALS is defined as the combined degeneration of the upper motor neurons (UMN) whose cell bodies are located in the motor cortex and that extend axons to the medulla and spinal cord, and lower motor neurons (LMN) whose cell bodies are located in the medulla and spinal cord, and that connect to the skeletal muscles
Determining where neurodegeneration starts may not be possible in patients due to technical limitations: (i) UMN signs may be harder to reveal than LMN signs, and LMN signs may partly mask UMN signs; (ii) while imaging techniques and magnetic resonance imaging (MRI) in particular are perfectly adapted to the study of the brain, they are harder to implement in the spinal cord; (iii) if LMN can be identified upon choline acetyltranferase (ChAT) staining in post-mortem tissues, there is still no marker to identify human UMN

Summary

Introduction

ALS is an incurable and fatal neurodegenerative disease that mostly starts in adulthood and rapidly progresses to paralysis and death within only 2–5 years of diagnosis [1]. ALS is defined as the combined degeneration of the upper motor neurons (UMN) whose cell bodies are located in the motor cortex and that extend axons to the medulla and spinal cord, and lower motor neurons (LMN) whose cell bodies are located in the medulla and spinal cord, and that connect to the skeletal muscles. This dual neuronal contribution is relevant given that ALS is the most severe disease of the adult motor system, in comparison with diseases that target UMN or LMN only [2]. No technique exists that allows neurologists or pathologists to compare the actual extent of UMN and LMN loss in ALS patients at one given time point

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