Emerging Evidence Highlighting the Importance of Redox Dysregulation in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS)

Abstract

The cellular redox state, or balance between cellular oxidation and reduction reactions, serves as a vital antioxidant defence system that is linked to all important cellular activities. Redox regulation is therefore a fundamental cellular process for aerobic organisms. Whilst oxidative stress is well described in neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), other aspects of redox dysfunction and their contributions to pathophysiology are only just emerging. ALS is a fatal neurodegenerative disease affecting motor neurons, with few useful treatments. Hence there is an urgent need to develop more effective therapeutics in the future. Here, we discuss the increasing evidence for redox dysregulation as an important and primary contributor to ALS pathogenesis, which is associated with multiple disease mechanisms. Understanding the connection between redox homeostasis, proteins that mediate redox regulation, and disease pathophysiology in ALS, may facilitate a better understanding of disease mechanisms, and lead to the design of better therapeutic strategies.

Deletion of Neuronal CuZnSOD Accelerates Age-Associated Muscle Mitochondria and Calcium Handling Dysfunction That Is Independent of Denervation and Precedes Sarcopenia

“…ROS can damage neurons [ 58 ], and the ability of neuronal cells to maintain their normal redox state diminishes during aging [ 59 ]. Substantial evidence supports the critical importance of redox homeostasis in normal functioning of the nervous system [ 60 ], and redox dysregulation contributes to numerous neurodegenerative diseases [ 61 ]. Moreover, declining neuronal mitochondrial respiratory capacity may also contribute to NMJ degeneration, as Hayes et al have reported an age-dependent loss of mitochondria from motor neurons in Sod1 -/- mice [ 62 ].…”

The use of fibroblasts as a valuable strategy for studying mitochondrial impairment in neurological disorders

“…Mitochondrial bioenergetics can also be affected in ALS [ 186 ]. According to this, examination of the ventral horn and the spinal motor neurons of ALS patients showed a significant decrease in MT-ND2 (Complex I) and MT-CO3 (Complex IV) genes, which could lead to the inhibition of ATP synthesis and motor neuronal degeneration [ 186 – 188 ]. Importantly, impairment of mitochondrial dynamics has been found in ALS, generating motor neuron toxicity and degeneration [ 19 , 185 , 189 , 190 ].…”

Biomolecular Modifications Linked to Oxidative Stress in Amyotrophic Lateral Sclerosis: Determining Promising Biomarkers Related to Oxidative Stress

“…Therefore, the development of more successful therapies is expected [70]. As preclinical studies of multiple therapeutic targets have used mutant SOD-1 mice, which do not exhibit TDP-43 pathology, which is a pathological hallmark of ALS, the results of the preclinical studies may not enhance survival and improve motor function in ALS patients [16]. Therefore, to develop more successful therapies, using cells and animals representing molecular abnormalities that occur in ALS patients in a preclinical study is important.…”

“…Since then, although a large number of pathogenic hypotheses have been proposed, oxidative stress has been considered one of the pathogenic hypotheses in ALS [15]. In addition, the evidence of perturbed cellular redox regulatory mechanisms and associated proteins in both sporadic and familial ALS is increasing [16]. Edaravone, a free radical scavenger that eliminates lipid peroxides and hydroxyl radicals, was recently approved for ALS patients, suggesting that modifying the redox regulation could be a therapeutic strategy for ALS [17].…”