Decoding the molecular mechanism underpinning motor neuron degeneration in ALS

Motor neuron degeneration is one of the main feature of different neuromuscular diseases, including Amyotrophic Lateral Sclerosis (ALS). The molecular mechanism underpinning motor neuron degeneration has not been well understood yet, hampering the development of successful therapeutic strategy. Lower Motor Neurons (LMNs) reside in the spinal cord and brainstem. Distinct classes of LMNs have been characterized and it has been shown that they degenerate with different rate during disease progression, with some subtype degenerating soon after disease onset, others staying functional even at late disease stages. Alpha motor neurons are the LMN class innervating extrafusal fibres of the muscle spindle, are responsible for muscle contraction, and are the neurons that degenerate first in ALS. On the other hand, gamma motor neurons innervate the intrafusal fibres and have a main role on the maintenance of muscular tone, and are spared even at late disease stages. The molecular aetiology below this phenomenon is not known. To fill this gap of knowledge, we will leverage on SODG93A mice as ALS mouse model to investigate the differentially expressed genes compared to WT mice, upon single-nuclei RNA sequencing. The aim of this study is to uncover the molecular underpinnings of LMN subtypes selective vulnerability in ALS.