Motor Neuron Susceptibility in ALS/FTD

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the death of both upper and lower motor neurons (MNs) in the brain, brainstem and spinal cord. The neurodegenerative mechanisms leading to MN loss in ALS are not fully understood. Importantly, the reasons why MNs are specifically targeted in this disorder are unclear, when the proteins associated genetically or pathologically with ALS are expressed ubiquitously. Furthermore, MNs themselves are not affected equally; specific MNs subpopulations are more susceptible than others in both animal models and human patients. Corticospinal MNs and lower somatic MNs, which innervate voluntary muscles, degenerate more readily than specific subgroups of lower MNs, which remain resistant to degeneration, reflecting the clinical manifestations of ALS. In this review, we discuss the possible factors intrinsic to MNs that render them uniquely susceptible to neurodegeneration in ALS. We also speculate why some MN subpopulations are more vulnerable than others, focusing on both their molecular and physiological properties. Finally, we review the anatomical network and neuronal microenvironment as determinants of MN subtype vulnerability and hence the progression of ALS.

Single-cell RNA-seq analysis of human iPSC-derived motor neurons resolves early and predictive ALS signatures

“…Here, we applied scRs to understand the heterogeneous and cell type-specific nature of disrupted physiology in human iPSC-based models of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by cortical and spinal motor neuron (MN) death that results in weakness and paralysis of voluntary muscles (Ragagnin et al, 2019;Swinnen and Robberecht, 2014). While numerous molecular pathways and cell types associated with ALS have been described, definitive mechanisms responsible for MN degeneration remain elusive (Taylor et al, 2016).…”

Phenotypic variability and its pathological basis in amyotrophic lateral sclerosis

“…B) . Not only systemic TDP‐43 dysfunction but also selective (region‐specific) susceptibility, especially of the motor neurons and frontotemporal system, could contribute to lesion formation and its progression . Moreover, the focal susceptibility related to onset may not be random, as it is determined by the age at onset and gender .…”

Protection from the Pathogenesis of Neurodegenerative Disorders, including Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Huntington’s Disease, and Parkinson’s Diseases, through the Mitigation of Reactive Oxygen Species

“…Indeed, in conjunction with mitochondrial dysfunction, ROS is considered a major cause of ALS. It is also noteworthy that OS not only raises overall RNS/ROS formation but also impacts the structure and conformation of various proteins, which then causes abnormal protein accumulation [210]. Oxidative stress biomarkers in CNS regions of paramount signi icance in the context of ALS are also indicative of their involvement in the degeneration of motor neurons [211].…”

“…Moreover, barring the issue of RNA toxicity, mitochondrial dysfunction appears to be correlated with all mechanisms of the toxicity characterizing ALS, such as de icient axonal transport, the erosion of homeostasis, and excitotoxicity [211]. Heightened levels of damage associated with ROS and RNS have been observed in ALS [210]. In addition, increased levels of ROS have been reported in the lymphoblasts of familial cases of ALS [212].…”