Review ArticleClinical perspective on oxidative stress in sporadic amyotrophic lateral sclerosis
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)
- et al.
Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
Neuron
(2011) - et al.
A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD
Neuron
(2011) - et al.
Reactive oxygen species, cellular redox systems, and apoptosis
Free Radic. Biol. Med.
(2010) Oxidative stress—from basic research to clinical application
Am. J. Med.
(1991)- et al.
Oxidative stress in ALS: key role in motor neuron injury and therapeutic target
Free Radic. Biol. Med.
(2010) - et al.
Beta-amyloid 42 accumulation in the lumbar spinal cord motor neurons of amyotrophic lateral sclerosis patients
Neurobiol. Dis.
(2005) - et al.
Neurodegeneration in amyotrophic lateral sclerosis: the role of oxidative stress and altered homeostasis of metals
Brain Res. Bull
(2003) Oxidative stress sensitivity in ALS muscle cells
Exp. Neurol.
(2009)- et al.
Oxidative stress in ALS: a mechanism of neurodegeneration and a therapeutic target
Biochim. Biophys. Acta
(2006) - et al.
Glutamate transporters are oxidant-vulnerable: a molecular link between oxidative and excitotoxic neurodegeneration?
Trends Pharmacol. Sci.
(1998)
Increased oxidative damage to DNA in ALS patients
Free Radic. Biol. Med.
8-Oxo-7,8-dihydroguanine: links to gene expression, aging, and defense against oxidative stress
Free Radic. Biol. Med.
Age-associated neurodegeneration and oxidative damage to lipids, proteins and DNA
Mol. Aspects Med.
An overview of lipid peroxidation with emphasis in outer segments of photoreceptors and the chemiluminescence assay
Int. J. Biochem. Cell Biol.
Dietary hydroxy fatty acids are absorbed in humans: implications for the measurement of “oxidative stress” in vivo
Free Radic. Biol. Med.
Genotoxicity of HNE
Mol. Aspects Med.
Neurotoxic lipid peroxidation species formed by ischemic stroke increase injury
Free Radic. Biol. Med.
Protein oxidation in aging, disease, and oxidative stress
J. Biol. Chem.
Protein tyrosine nitration—functional alteration or just a biomarker?
Free Radic. Biol. Med.
Protein nitration in a mouse model of familial amyotrophic lateral sclerosis: possible multifunctional role in the pathogenesis
J. Biol. Chem.
Increase in oxidized NO products and reduction in oxidized glutathione in cerebrospinal fluid from patients with sporadic form of amyotrophic lateral sclerosis
Neurosci. Lett.
Blood oxidative stress in amyotrophic lateral sclerosis
J. Neurol. Sci.
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.
An increase of oxidized coenzyme Q-10 occurs in the plasma of sporadic ALS patients
J. Neurol. Sci.
Increased mitochondrial oxidative damage in patients with sporadic amyotrophic lateral sclerosis
J. Neurol. Sci.
Low uric acid levels in serum of patients with ALS: further evidence for oxidative stress?
J. Neurol. Sci.
Time course of oxidant markers and antioxidant defenses in subgroups of amyotrophic lateral sclerosis patients
Neurochem. Int.
Environmental exposure to trace elements and risk of amyotrophic lateral sclerosis: a population-based case–control study
Environ. Res.
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
Amyotrophic lateral sclerosis
Curr. Opin. Neurol.
Palliative care for patients with amyotrophic lateral sclerosis—"prepare for the worst and hope for the best."
JAMA
Familial amyotrophic lateral sclerosis, a historical perspective
Acta Myol
Mutation analysis of VCP in familial and sporadic amyotrophic lateral sclerosis
Neurobiol. Aging
Clinical genetics of amyotrophic lateral sclerosis: what do we really know?
Nat. Rev. Neurol.
Mutations of optineurin in amyotrophic lateral sclerosis
Nature
Current hypotheses for the underlying biology of amyotrophic lateral sclerosis
Ann. Neurol
Recent advances in motor neuron disease
Curr. Opin. Neurol.
Oxidative stress and nitration in neurodegeneration: cause, effect, or association?
J. Clin. Invest.
Oxidative stress: oxidants and antioxidants
Exp. Physiol.
The kinetics of the autoxidation of polyunsaturated fatty acids
Lipids
Oxidative stress in neurodegeneration: mechanisms and therapeutic perspectives
Curr. Top. Med. Chem.
Relevance of oxidative injury in the pathogenesis of motor neuron diseases
Amyotrophic Lateral Scler. Other Mot. Neuron Disord.
Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue
Ann. Neurol.
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.
PARP expression is increased in astrocytes but decreased in motor neurons in the spinal cord of sporadic ALS patients
J. Neuropathol. Exp. Neurol
Molecular and cellular pathways of neurodegeneration in motor neurone disease
J. Neurol. Neurosurg. Psychiatry
Oxidative stress in amyotrophic lateral sclerosis
J. Neurol.
Oxidative stress: a common denominator in the pathogenesis of amyotrophic lateral sclerosis
Curr. Opin. Rheumatol
Cited by (258)
Pharmacokinetics of Edaravone Oral Suspension in Patients With Amyotrophic Lateral Sclerosis
2023, Clinical TherapeuticsNanomedicine innovations in spinal cord injury management: Bridging the gap
2023, Environmental ResearchMetal ratios as possible biomarkers for amyotrophic lateral sclerosis
2023, Journal of Trace Elements in Medicine and BiologyLevels of 24-hydroxycholesteryl esters in cerebrospinal fluid and plasma from patients with amyotrophic lateral sclerosis
2023, Journal of Pharmaceutical and Biomedical Analysis