Elsevier

Free Radical Biology and Medicine

Volume 65, December 2013, Pages 509-527
Free Radical Biology and Medicine

Review Article
Clinical perspective on oxidative stress in sporadic amyotrophic lateral sclerosis

https://doi.org/10.1016/j.freeradbiomed.2013.06.029Get rights and content

Highlights

  • Oxidative stress is a key pathogenic mechanism of motoneuronal degeneration in ALS.

  • Oxidative stress biomarkers are increased in CSF, plasma, and urine in ALS.

  • Many environmental risk factors in ALS can cause systemic oxidative stress.

  • Malnutrition and respiratory and psychological stress may cause oxidative stress.

  • Increased systemic oxidative stress may quicken ALS disease progression.

Abstract

Sporadic amyotrophic lateral sclerosis (ALS) is one of the most devastating neurological diseases; most patients die within 3 to 4 years after symptom onset. Oxidative stress is a disturbance in the pro-oxidative/antioxidative balance favoring the pro-oxidative state. Autopsy and laboratory studies in ALS indicate that oxidative stress plays a major role in motor neuron degeneration and astrocyte dysfunction. Oxidative stress biomarkers in cerebrospinal fluid, plasma, and urine are elevated, suggesting that abnormal oxidative stress is generated outside of the central nervous system. Our review indicates that agricultural chemicals, heavy metals, military service, professional sports, excessive physical exertion, chronic head trauma, and certain foods might be modestly associated with ALS risk, with a stronger association between risk and smoking. At the cellular level, these factors are all involved in generating oxidative stress. Experimental studies indicate that a combination of insults that induce modest oxidative stress can exert additive deleterious effects on motor neurons, suggesting that multiple exposures in real-world environments are important. As the disease progresses, nutritional deficiency, cachexia, psychological stress, and impending respiratory failure may further increase oxidative stress. Moreover, accumulating evidence suggests that ALS is possibly a systemic disease. Laboratory, pathologic, and epidemiologic evidence clearly supports the hypothesis that oxidative stress is central in the pathogenic process, particularly in genetically susceptive individuals. If we are to improve ALS treatment, well-designed biochemical and genetic epidemiological studies, combined with a multidisciplinary research approach, are needed and will provide knowledge crucial to our understanding of ALS etiology, pathophysiology, and prognosis.

Introduction

Amyotrophic lateral sclerosis (ALS) is one of the most devastating neurological diseases. Patients with ALS develop relentlessly progressive paralysis that involves all the skeletal muscles, as well as the bulbar and respiratory muscles. This paralysis ultimately leads to the patient’s death on average 40 months after symptom onset. Riluzole is the only medication that has received Food and Drug Administration approval, but it has only modest benefits at best [1], [2], [3]. More than a dozen molecular mutations have been discovered in familial ALS (fALS), which constitutes 5 to 10% of all ALS cases [4], [5], [6], [7], [8], [9]. In contrast, despite decades of intense research and a number of highly plausible hypotheses [10], [11], [12], still little is known regarding factors related to the causes or risks of developing sporadic ALS (sALS), which we focus on in this review.

Our review is specifically focused on clinical, or patient-oriented, research in oxidative stress in sALS. Because discussing oxidative stress on the basic science level is not our objective, we provide a few excellent reviews here for this information [13], [14], [15]. First, we briefly discuss the effects of oxidative stress on motor neurons and the central nervous system (CNS). Moreover, we review currently available biomarkers that are useful for investigating oxidative stress in sALS and the potential consequences of oxidized products. Then, we examine epidemiological studies and how environmental and lifestyle factors potentially trigger oxidative stress in exposed individuals. We also discuss evidence that oxidative stress is not just an event in the CNS but rather a systemic process, although the CNS and motor neurons may be most vulnerable to systemic oxidative stress. Because oxidative stress results from a pro- and antioxidative imbalance [15], [16], current knowledge of intrinsic antioxidative mechanisms is reviewed along with possible interactions between oxidative stress and modifier genes in sALS. We close with a call for molecular epidemiology studies in ALS. We hope that this review will stimulate more research in patients with ALS that investigates the relationship between sALS pathogenesis and environmental exposures related to oxidative stress, which will ultimately lead to novel therapeutic approaches and better clinical management.

Section snippets

Motor neuron degeneration in ALS

The CNS as a whole is particularly susceptible to oxidative stress because the neuronal membrane contains a high abundance of polyunsaturated fatty acids, especially arachidonic and docosahexaenoic acids; it consumes oxygen at a high rate; and it contains high concentrations of redox-active transition metals but a relatively (compared to the oxidative stress level) low concentration of antioxidants [17], [18]. In sALS, at the cellular level, genetic factors, excitotoxicity, apoptosis,

Oxidative stress biomarkers available for studies in ALS

Whereas oxidative stress seems to be closely associated with motor neuron degeneration in ALS, it still remains unsettled whether oxidative stress is involved outside of the CNS, such as in skeletal muscles [28], [42], [43]. Reliable oxidative stress biomarkers are the first essential step to ascertaining such extra-CNS involvement [42]. Oxidative stress damages critical cellular macromolecules, which can eventually lead to cell death by necrosis or apoptosis [44]. The localization and effects

Environmental and lifestyle risk factors associated with sALS

In this section, we review environmental exposures and lifestyle factors that have been associated with ALS that also may be mechanistically involved with underlying oxidative stress. Table 2 summarizes potential relationships among environmental and lifestyle factors and sALS and oxidative stress.

Intrinsic antioxidants

Little is known about the role of intrinsic antioxidants in sALS. Serum total antioxidant status, a measure of peroxyl adduct-scavenging capacity, has been reported to be significantly (P<0.05) higher in ALS patients (n=28) compared with healthy controls (n=20) but did not correlate with ALS onset phenotype, disease duration, or clinical state [220]. More recently, the TBARS concentration and antioxidants such as SOD1, catalase, GSH peroxidase, GSH reductase, and glucose-6-phosphate

Modifier genes associated with sALS and oxidative stress

In addition to PON1, other possible genetic factors modifying sALS disease expression have been reported: ApoE, survival motor neuron (SMN), inducers of angiogenesis (such as VEGF and angiogenin (ANG)), and other genes involved in the regulation of many cellular processes, including some of the known RNA processes (e.g., transcription and posttranscriptional and translational regulation).

The role of ApoE in sALS is uncertain. It was suggested that the ε4 allele has a deleterious effect on ALS

Gene mutations in fALS other than SOD1

Most gene mutations found in fALS cause mutated protein accumulation, aggregation, or both, which is likely to result in endoplasmic reticulum (ER) stress, a new area of ALS research [293]. Particularly, vesicle-associated protein-associated protein B, whose mutation causes a rare form of fALS, is required for ER activation during ER stress and participates in intracellular vesicle transport. Other rare mutations occur in valosin-containing protein, essential for ubiquitin-dependent protein

Disease progression and oxidative stress

The mean survival in sALS is approximately 40 months after symptom onset, but the duration of survival and functional prognosis vary widely, as approximately 10% of patients live beyond 10 years after symptom onset [298]. The reasons for this variability are enigmatic. The most consistent finding is that the longer the duration between symptom onset and diagnosis, the longer the survival, a relationship that may be partly attributable to biological variability: the slower the disease

sALS as a systemic disease

Although motor neurons are selectively affected in sALS, the possibility that sALS might be part of a systemic disease in which motor neurons are especially vulnerable has been postulated for some time [320], [321]. A number of well-established abnormalities in sALS occur in the immune system, skin and skeletal muscle tissue, and lipid metabolism [28], [321], [322], [323], [324], [325]. Concentrations of proinflammatory cytokines, such as MCP-1 [79], [326] and IL-6 [327], are elevated in sALS

What is the next step?

Although the evidence for oxidative damage in sALS pathogenesis is extensive, the ultimate trigger(s) that causes increased ROS levels is still unknown, leading to speculation as to whether oxidative stress is a primary cause of disease or merely a secondary consequence. Furthermore, it is always possible that there may be unrecognized alternative mechanisms that can, in part, explain the pathogenic changes described above. Prospective studies have shown that smoking, a cause of oxidative

Acknowledgments

Georgia Christodoulou, M.A., helped with the manuscript preparation and Cassandra Talerico, Ph.D., provided substantive editing. We acknowledge grant support from the NIEHS (1R01 ES016348 to Hiroshi Mitsumoto and P30 ES009089 to Regina Santella) and, also to H.M., from the Muscular Dystrophy Association (No. 4350), MDA Wings Over Wall Street, and The Judith and Jean Pape Adams Charitable Foundation, along with donations from the Spina Family, David Marren, the Senerchia family, the Drago

References (357)

  • M Bogdanov et al.

    Increased oxidative damage to DNA in ALS patients

    Free Radic. Biol. Med.

    (2000)
  • Z Radak et al.

    8-Oxo-7,8-dihydroguanine: links to gene expression, aging, and defense against oxidative stress

    Free Radic. Biol. Med.

    (2010)
  • Z Radak et al.

    Age-associated neurodegeneration and oxidative damage to lipids, proteins and DNA

    Mol. Aspects Med.

    (2011)
  • A. Catala

    An overview of lipid peroxidation with emphasis in outer segments of photoreceptors and the chemiluminescence assay

    Int. J. Biochem. Cell Biol.

    (2006)
  • R Wilson et al.

    Dietary hydroxy fatty acids are absorbed in humans: implications for the measurement of “oxidative stress” in vivo

    Free Radic. Biol. Med.

    (2002)
  • PM. Eckl

    Genotoxicity of HNE

    Mol. Aspects Med.

    (2003)
  • SLH Zeiger et al.

    Neurotoxic lipid peroxidation species formed by ischemic stroke increase injury

    Free Radic. Biol. Med.

    (2009)
  • BS Berlett et al.

    Protein oxidation in aging, disease, and oxidative stress

    J. Biol. Chem.

    (1997)
  • JM Souza et al.

    Protein tyrosine nitration—functional alteration or just a biomarker?

    Free Radic. Biol. Med.

    (2008)
  • F Casoni et al.

    Protein nitration in a mouse model of familial amyotrophic lateral sclerosis: possible multifunctional role in the pathogenesis

    J. Biol. Chem.

    (2005)
  • H Tohgi et al.

    Increase in oxidized NO products and reduction in oxidized glutathione in cerebrospinal fluid from patients with sporadic form of amyotrophic lateral sclerosis

    Neurosci. Lett.

    (1999)
  • D Bonnefont-Rousselot et al.

    Blood oxidative stress in amyotrophic lateral sclerosis

    J. Neurol. Sci.

    (2000)
  • H Ryberg et al.

    Cerebrospinal fluid levels of free 3-nitrotyrosine are not elevated in the majority of patients with amyotrophic lateral sclerosis or Alzheimer's disease

    Neurochem. Int.

    (2004)
  • M Sohmiya et al.

    An increase of oxidized coenzyme Q-10 occurs in the plasma of sporadic ALS patients

    J. Neurol. Sci.

    (2005)
  • T Murata et al.

    Increased mitochondrial oxidative damage in patients with sporadic amyotrophic lateral sclerosis

    J. Neurol. Sci.

    (2008)
  • D Keizman et al.

    Low uric acid levels in serum of patients with ALS: further evidence for oxidative stress?

    J. Neurol. Sci.

    (2009)
  • E Cova et al.

    Time course of oxidant markers and antioxidant defenses in subgroups of amyotrophic lateral sclerosis patients

    Neurochem. Int.

    (2010)
  • M Bergomi et al.

    Environmental exposure to trace elements and risk of amyotrophic lateral sclerosis: a population-based case–control study

    Environ. Res.

    (2002)
  • RG Miller et al.

    Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology

    Neurology

    (2009)
  • AC Ludolph et al.

    Amyotrophic lateral sclerosis

    Curr. Opin. Neurol.

    (2012)
  • H Mitsumoto et al.

    Palliative care for patients with amyotrophic lateral sclerosis—"prepare for the worst and hope for the best."

    JAMA

    (2007)
  • T Siddique et al.

    Familial amyotrophic lateral sclerosis, a historical perspective

    Acta Myol

    (2011)
  • KL Williams et al.

    Mutation analysis of VCP in familial and sporadic amyotrophic lateral sclerosis

    Neurobiol. Aging

    (2011)
  • PM Andersen et al.

    Clinical genetics of amyotrophic lateral sclerosis: what do we really know?

    Nat. Rev. Neurol.

    (2011)
  • H Maruyama et al.

    Mutations of optineurin in amyotrophic lateral sclerosis

    Nature

    (2010)
  • JD. Rothstein

    Current hypotheses for the underlying biology of amyotrophic lateral sclerosis

    Ann. Neurol

    (2009)
  • P Van Damme et al.

    Recent advances in motor neuron disease

    Curr. Opin. Neurol.

    (2009)
  • Rowland LP. The causes of sporadic amyotrophic lateral sclerosis. In: Mitsumoto H, Przedborski S, Gordon PH, Eds....
  • H Ischiropoulos et al.

    Oxidative stress and nitration in neurodegeneration: cause, effect, or association?

    J. Clin. Invest.

    (2003)
  • H. Sies

    Oxidative stress: oxidants and antioxidants

    Exp. Physiol.

    (1997)
  • JP Cosgrove et al.

    The kinetics of the autoxidation of polyunsaturated fatty acids

    Lipids

    (1987)
  • A. Contestabile

    Oxidative stress in neurodegeneration: mechanisms and therapeutic perspectives

    Curr. Top. Med. Chem.

    (2001)
  • J Agar et al.

    Relevance of oxidative injury in the pathogenesis of motor neuron diseases

    Amyotrophic Lateral Scler. Other Mot. Neuron Disord.

    (2003)
  • JS Henkel et al.

    Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue

    Ann. Neurol.

    (2004)
  • S Kato et al.

    Redox system expression in the motor neurons in amyotrophic lateral sclerosis (ALS): immunohistochemical studies on sporadic ALS, superoxide dismutase 1 (SOD1)-mutated familial ALS, and SOD1-mutated ALS animal models

    Acta Neuropathol.

    (2005)
  • SH Kim et al.

    PARP expression is increased in astrocytes but decreased in motor neurons in the spinal cord of sporadic ALS patients

    J. Neuropathol. Exp. Neurol

    (2003)
  • Beckman JS, Estevez AG. Superoxide dismutase, oxidative stress, and ALS. In: Mitsumoto H, Przedborski S, Gordon PH,...
  • PJ. Shaw

    Molecular and cellular pathways of neurodegeneration in motor neurone disease

    J. Neurol. Neurosurg. Psychiatry

    (2005)
  • W. Robberecht

    Oxidative stress in amyotrophic lateral sclerosis

    J. Neurol.

    (2000)
  • EP Simpson et al.

    Oxidative stress: a common denominator in the pathogenesis of amyotrophic lateral sclerosis

    Curr. Opin. Rheumatol

    (2003)
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