Review Article
Oxidative stress in ALS: Key role in motor neuron injury and therapeutic target

https://doi.org/10.1016/j.freeradbiomed.2009.11.018Get rights and content

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by death of motor neurons leading to muscle wasting, paralysis, and death, usually within 2–3 years of symptom onset. The causes of ALS are not completely understood, and the neurodegenerative processes involved in disease progression are diverse and complex. There is substantial evidence implicating oxidative stress as a central mechanism by which motor neuron death occurs, including elevated markers of oxidative damage in ALS patient spinal cord and cerebrospinal fluid and mutations in the antioxidant enzyme superoxide dismutase 1 (SOD1) causing approximately 20% of familial ALS cases. However, the precise mechanism(s) by which mutant SOD1 leads to motor neuron degeneration has not been defined with certainty, and the ultimate trigger for increased oxidative stress in non-SOD1 cases remains unclear. Although some antioxidants have shown potential beneficial effects in animal models, human clinical trials of antioxidant therapies have so far been disappointing. Here, the evidence implicating oxidative stress in ALS pathogenesis is reviewed, along with how oxidative damage triggers or exacerbates other neurodegenerative processes, and we review the trials of a variety of antioxidants as potential therapies for ALS.

Introduction

Amyotrophic lateral sclerosis (ALS), often referred to more generally as motor neuron disease or Lou Gehrig's disease, is among the most common adult-onset neurodegenerative diseases. ALS typically develops between 50 and 60 years of age as a relentless progressive neuromuscular failure, caused by degeneration of both upper motor neurons in the motor cortex and lower motor neurons connecting the spinal cord and brain stem to muscle fibers, leading to muscle denervation and atrophy [1]. Symptoms often initially present in one motor neuron population, but will spread to contiguous motor neuron groups. Although variants of the disease may apparently affect a discrete motor neuron population, such as only lower motor neurons, upper motor neurons, or bulbar motor neurons innervating muscles that control speech, chewing, and swallowing, signs of both upper and lower motor neuron dysfunction develop in the majority of patients as the disease progresses. Certain motor neuron populations are less vulnerable, specifically those in the upper brain-stem nuclei that control eye movements and those in Onuf's nucleus in the sacral spinal cord controlling the pelvic floor muscles. The rate of disease progression varies between individuals and can be influenced by the site of onset, but is usually rapid, with an average survival of only 2–3 years from symptom onset. The major cause of death is respiratory failure. ALS pathology is characterized by loss of motor neurons, with ubiquitinated inclusions, abnormal mitochondria, and neurofilament aggregates in surviving motor neurons, and glial activation. Riluzole, the only drug currently licensed as a neuroprotective agent for ALS, extends life expectancy by only approximately 3 months.

Section snippets

Causes of ALS

The cause of disease is unknown in the majority of ALS cases, which are described as being sporadic (SALS), although 5–10% of cases are genetic and are classified as familial (FALS). The etiology of SALS is largely unknown, and the worldwide incidence of disease is fairly uniform at around 1–2/100,000 in most populations [2]. The exceptions to this are the Western Pacific island of Guam and the Kii peninsula of Japan, where the incidence has been much higher, possibly linked to an environmental

Evidence for oxidative stress in ALS

Oxidative stress arises from an imbalance between the production of reactive oxygen species (ROS) and the ability of the system to remove or repair the damage caused and restore the prevailing reducing environment. Cellular ROS arise as by-products of aerobic metabolism [18], [19], [20], mostly due to leakage of electrons from the mitochondrial respiratory chain, resulting in incomplete reduction of molecular oxygen during oxidative phosphorylation, to produce the superoxide radical anion (O2⋅−

Sources of oxidative stress in ALS

The upstream cause of disease is unknown in the majority of ALS cases, so researchers are limited to working on the pathogenic mechanisms that have been implicated during disease progression. This has led to a debate as to whether oxidative stress is a primary cause of degeneration or whether it is merely a consequence of some other toxic insult. One of the few clearly identified risk factors for developing ALS is increasing age, with few cases being diagnosed before the age of 50 years.

Cross talk between oxidative stress and other pathogenic mechanisms

The pathogenic processes involved in ALS are complex, multifactorial, and incompletely understood. What is clear is that motor neuron death occurs not as the result of a single insult, but rather through a combination of mechanisms including not only oxidative stress, but also excitotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, protein aggregation, cytoskeletal dysfunction, involvement of nonneuronal cells, and defects in RNA processing and trafficking. Given the complexity

Selective vulnerability of motor neurons

Motor neurons are not the only cell type to be affected in ALS, but the major consequence of these effects is the selective death of motor neuron populations, leaving other cell types largely unaffected. Why motor neurons are particularly affected is not completely understood, although aspects of their structural and metabolic specialization probably at least partially explain this vulnerability [193]. Motor neurons are unusually large, with a cell body of approximately 50–60 μm and an axon of

Antioxidant therapeutic strategies

There is a long history of oxidative stress as a therapeutic target in ALS and many patients take dietary antioxidants on the advice of their physician. However, a Cochrane systematic review of randomized or quasi-randomized controlled trials of antioxidant treatment for ALS found no significant effect on any of the outcome measures considered, although it was stated that antioxidant trials have generally been of poor methodological quality and lacking in statistical power [200]. Any

Summary

Although the evidence for oxidative damage in ALS pathogenesis is extensive, the ultimate trigger(s) that causes increased ROS levels is still largely unknown, leading to speculation as to whether oxidative stress is a primary cause of disease or merely a secondary consequence. However, given that any treatment could be started only after the onset of clinical symptoms and diagnosis, it is not the underlying cause of oxidative stress that matters, but the downstream effects of it, which are

Acknowledgment

This work was funded by a program award from the Wellcome Trust to P.J.S.

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