Oxidative Stress in Amyotrophic Lateral Sclerosis: Pathophysiology and Opportunities for Pharmacological Intervention

Abstract

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease or Charcot disease, is a fatal neurodegenerative disease that affects motor neurons (MNs) and leads to death within 2–5 years of diagnosis, without any effective therapy available. Although the pathological mechanisms leading to ALS are still unknown, a wealth of evidence indicates that an excessive reactive oxygen species (ROS) production associated with an inefficient antioxidant defense represents an important pathological feature in ALS. Substantial evidence indicates that oxidative stress (OS) is implicated in the loss of MNs and in mitochondrial dysfunction, contributing decisively to neurodegeneration in ALS. Although the modulation of OS represents a promising approach to protect MNs from degeneration, the fact that several antioxidants with beneficial effects in animal models failed to show any therapeutic benefit in patients raises several questions that should be analyzed. Using specific queries for literature search on PubMed, we review here the role of OS-related mechanisms in ALS, including the involvement of altered mitochondrial function with repercussions in neurodegeneration. We also describe antioxidant compounds that have been mostly tested in preclinical and clinical trials of ALS, also describing their respective mechanisms of action. While the description of OS mechanism in the different mutations identified in ALS has as principal objective to clarify the contribution of OS in ALS, the description of positive and negative outcomes for each antioxidant is aimed at paving the way for novel opportunities for intervention. In conclusion, although antioxidant strategies represent a very promising approach to slow the progression of the disease, it is of utmost need to invest on the characterization of OS profiles representative of each subtype of patient, in order to develop personalized therapies, allowing to understand the characteristics of antioxidants that have beneficial effects on different subtypes of patients.

Dysregulations of Expression of Genes of the Ubiquitin/SUMO Pathways in an In Vitro Model of Amyotrophic Lateral Sclerosis Combining Oxidative Stress and SOD1 Gene Mutation

“…Oxidative damages are a consequence of an imbalance between a production of reactive oxygen species (ROS) and the ability of motor neurons/glial cells to reduce the level of ROS. Evidence of oxidative damages in ALS includes protein, lipid, and DNA oxidation observed in spinal cord and cerebrospinal fluid from ALS patients [ 7 , 8 , 9 , 10 , 11 ].…”

Deubiquitinating enzymes (DUBs): Regulation, homeostasis, and oxidative stress response

“…This emphasizes the importance of DUB activity during the recovery from oxidative stress, particularly as redox regulation of the DUBs themselves can therefore determine the duration of stress granule retention, depending on the speed of DUB oxidation reversal. Furthermore, both stress granule formation and oxidative stress have been implicated in neurological disorders such as amyotrophic lateral sclerosis and spinocerebellar ataxia type 2, and DUBs could therefore be a common element between both of these factors ( 25 , 222 , 223 , 224 , 225 ).…”

Elucidating the Multi-Targeted Role of Nutraceuticals: A Complementary Therapy to Starve Neurodegenerative Diseases

“…Moreover, the overload of transition metals (such as iron) has been implicated in the Lewy body formation process in Parkinson’s [ 65 ]. OS-induced damage to DNA, proteins, and lipids and mutations in the SOD-1(Cu/Zn)-encoding gene have been linked with sporadic and familial amyotrophic lateral sclerosis forms [ 66 ]. The pathology of multiple sclerosis is not dissimilar when the harmful influence of OS is considered.…”