Oxidative Stress, Neuroinflammation and Mitochondria in the Pathophysiology of Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron (MN) disease. Its primary cause remains elusive, although a combination of different causal factors cannot be ruled out. There is no cure, and prognosis is poor. Most patients with ALS die due to disease-related complications, such as respiratory failure, within three years of diagnosis. While the underlying mechanisms are unclear, different cell types (microglia, astrocytes, macrophages and T cell subsets) appear to play key roles in the pathophysiology of the disease. Neuroinflammation and oxidative stress pave the way leading to neurodegeneration and MN death. ALS-associated mitochondrial dysfunction occurs at different levels, and these organelles are involved in the mechanism of MN death. Molecular and cellular interactions are presented here as a sequential cascade of events. Based on our present knowledge, the discussion leads to the idea that feasible therapeutic strategies should focus in interfering with the pathophysiology of the disease at different steps.

Human Paraoxonase-2 (PON2): Protein Functions and Modulation

“…ALS is a multifactorial disease characterized by cerebral cell dysfunction and mitochondrial alteration. It is associated with the progressive increase in neuroinflammation, generalized oxidative stress, and metabolic alterations [186,187]. Saeed et al [188] identified high linkage disequilibrium in PON2 and PON3 genes.…”

Power Failure of Mitochondria and Oxidative Stress in Neurodegeneration and Its Computational Models

“…Progressive motor neuron loss leads to muscle weakness, then muscle atrophy, spasticity, eventual paralysis and finally death 3 to 5 years after diagnosis by denervation of the respiratory muscles [ 40 ]. ALS-associated mitochondrial dysfunction occurs at different levels, including ROS production, defective oxidative phosphorylation, oxidative stress, and defective mitochondrial dynamics [ 8 ]. Superoxide (O 2 − ) and nitric oxide (NO), two key pathogenic components produced by the electron transport system (ETS), leads to oxidative damage such as DNA oxidation, protein oxidation, and lipid peroxidation [ 9 , 41 ].…”

“…Aging and environmental stressors attenuate brain cell function to neutralize ROS and in consequence, oxidative stress disrupts cellular homeostasis and triggers the progression of neurodegeneration. The vicious cycle of oxidative stress is known to be the most common pathogenesis in neurodegenerative disorders including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Parkinson’s disease (PD), and others [ 3 , 7 , 8 , 9 ]. In this review, we discuss which molecules and stressors affect mitochondrial function and how oxidative stress is linked to the pathophysiology and neurodegeneration of AD, ALS, HD, and PD, respectively [ 3 , 7 , 8 , 9 , 10 ].…”

Paraoxonase Role in Human Neurodegenerative Diseases

“…ALS is a multifactorial disease characterized by cerebral cell dysfunction and mitochondrial alteration. It is associated with the progressive increase in neuroinflammation, generalized oxidative stress and metabolic alterations [ 156 , 157 ]. Saeed et al [ 158 ] have shown a significant link between the polymorphisms present in the PON gene and ALS.…”