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

• Published in: Brain sciences Vol. 11; no. 3; p. 369
• Main Authors: Marques, Christine, Burg, Thibaut, Scekic-Zahirovic, Jelena, Fischer, Mathieu, Rouaux, Caroline
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 13.03.2021; MDPI
• Subjects: Amyotrophic lateral sclerosis; Animals; Artificial chromosomes; Brain stem; Cortex (motor); descending propagation; Disease; Electrophysiology; Gene expression; Labeling; Life Sciences; lower motor neurons; Molecular modelling; motor cortex; Motor neurons; Neurodegeneration; Neurodegenerative diseases; Neurons; somatotopy; Spinal cord; Statistical analysis; Superoxide dismutase; Temporal lobe; upper motor neurons; United States > US; Germany; motor cortex; somatotopy; upper motor neurons; dying-forward; amyotrophic lateral sclerosis; descending propagation; lower motor neurons
• ISSN: 2076-3425; 2076-3425
• DOI: 10.3390/brainsci11030369

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.