Current insights in the molecular genetic pathogenesis of amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that leads to the massive loss of motor neurons in cerebrum, brain stem and spinal cord. It affects not only motor neurons but also other neurons and glial cells, resulting in the progressive muscle atrophy, the severe disability and the eventual death due to the respiratory failure. The pathogenesis of ALS is not fully understood. Currently, several factors are considered to be involved in the pathogenesis of ALS, such as genetic factors, imbalances in protein homeostasis, RNA metabolism disorders, mitochondrial dysfunctions, glutamate-mediated excitatory toxicities and intra-neuronal material transport disorders in neurons. The study of genetic mutations related to ALS pathogenesis will link the molecular and cellular mechanisms of the disease, thus enhancing the understanding of its occurrence and progression, thereby providing new insights for the pathogenesis of ALS. This review summarizes the current insights in the molecular genetic pathogenesis of ALS.

Keywords: amyotrophic lateral sclerosis; genetics; molecule; pathogenesis; proteomics.

Figure 1

The pathogenesis of ALS involves complex processes with multiple genes and multiple pathways dysfunction, such as the imbalance of protein homeostasis in neurons, the disorder of RNA metabolism, the mitochondrial dysfunction, the glutamate-mediated excitatory toxicity and the disturbance of intra-neuronal material transport. So far, more than 50 genes have been found to be associated with ALS. Among them, C9orf72, SOD1, TDP-43, and FUS genes were most closely related to the pathogenesis of ALS. The mutations of various related genes play the different roles in the different pathways in the pathogenesis of ALS, which are interrelated and act together to lead to the occurrence and development pathogenesis of ALS.

Figure 2

The mutations in genes such as SOD1, C9orf72, TDP-43, ubiquilin-2, and VCP can interfere with the UPS and autophagy degradation pathways, leading to the abnormal accumulation of toxic proteins and then leading to the protein homeostasis imbalance and ultimately inducing the cell death.

Figure 3

The FUS mutations mainly cause the mislocalization of FUS in cytoplasm, resulting in the FUS immunoreactive inclusion bodies. The abnormal RNA splicing pathway caused by the TDP-43 mutation or the nuclear TDP-43 depletion promotes the pathways of ALS occurrence through the TDP-43 functional loss and/or toxicity enhancement.

Figure 4

Both TDP-43 and FUS mutant isoforms, respectively, disrupt the mitochondrial RNA expression and interact with the mitochondrial ATP synthase catalytic subunits, resulting in the abnormal mitochondrial membrane potential, and reducing the ATP production and the oxygen consumption. The SOD1 mutations impair the ability of mitochondria to eliminate ROS. The C9orf72 mutations increase the concentration of neuronal Ca²⁺ influx and the overexpression of polyGR that causes the mitochondrial dysfunction by altering protein binding patterns on mitochondria. The Sigma-1R mutants cannot bind to IP3R, leading to the Ca²⁺ imbalance in MAM and exacerbating the related pathways of ER stress-induced neuronal death.

Figure 5

The mutation TDP-43 inhibits the mitochondrial RNA expression, resulting in the mitochondrial crest damage, decreasing the respiratory chain complex I and IV activity, and decreasing the ATP synthesis.

Figure 6

The SOD1 mutants enhance the caspase-3-mediated cleavage of EAAT2 (GLT-1), resulting in impairing the glutamate uptake and producing excitotoxicity in the pathogenesis of ALS. In addition, C9orf72 mutations lead to the production of toxic dipeptide repeat sequences, increasing the expression and Ca²⁺ permeability of GluA1, leading to excitotoxicity in motor neurons in the pathogenesis of ALS.

Figure 7

The C9orf72 gene mutations can affect the vesicular transport pathway, reduce the protein degradation, and cause the neurodegeneration and death of neurons. The TDP-43 gene deletion reduces the signaling pathways for the epidermal growth factor receptors and the serine/threonine kinase receptors, affecting the neuron survival and the axon innervation. In addition, it also interferences with the material circulation and target protein transport pathways on the neuronal cell membrane, ultimately damaging neurons.