Increased lipid peroxidation in sera of ALS patients

Simpson, Ericka; Henry, Yves-Dominique; Henkel, Jenny S.; Smith, Robert G.; Appel, Stanley H.

doi:10.1212/wnl.62.10.1758

Cited by 291 publications

(183 citation statements)

References 56 publications

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“…Oxidative stress is now widely believed to be involved in the pathogenesis of major age-related diseases such as neurodegenerative diseases [9][10][11][12][13][14][15][16], cancer [17,18] and a long list of several other human diseases such as ischemia-reperfusion injury [19], stroke [20,21], hypertension [3], diabetes [22], rheumatic diseases [23][24][25] and multiple sclerosis [26].…”

Section: Reactive Oxygen Species and Oxidative Stressmentioning

confidence: 99%

“…On the other hand, CNS has high content of polyunsaturated fatty acids, which are very prone to oxidative damage and also contains large amounts of iron, which is involved in the formation of dangerous ROS like hydroxyl radical [12]. A large body of evidence exists on the involvement of oxidative stress in the pathogenesis of Alzheimer disease [9,10,12,13], Parkinson disease [11,16] and amyotrophic lateral sclerosis (ALS) [14].…”

Section: Neurodegenerative Diseasesmentioning

confidence: 99%

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Clinical and pharmacological aspects of bath salt use: A review of the literature and case reports

Miotto¹,

Striebel²,

Cho

et al. 2013

Drug and Alcohol Dependence

121

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Abstract:Reactive oxygen species (ROS) are widely believed to cause or aggravate several human pathologies such as neurodegenerative diseases, cancer, stroke and many other ailments. Antioxidants are assumed to counteract the harmful effects of ROS and therefore prevent or treat oxidative stress-related diseases. In this report, recent human studies exploring the efficiency of antioxidants in prevention and treatment of various diseases are reviewed. Few antioxidants including edaravone (for ischemic stroke in Japan), Nacetylcysteine (for acetaminophen toxicity), alfa-lipoic acid (for diabetic neuropathy) and some flavonoids (polyphenolic compounds present in dietary plants), such as micronized purified flavonoid fraction (diosmin and hesperidin) and oxerutins (for chronic venous insufficiency) as well as baicalein and catechins (for osteoarthritis) have found accepted clinical use. However, despite much enthusiasm in the 1980s and 1990s, many well-known agents such as antioxidant vitamins and also more recently developed compounds such as nitrones have not successfully passed the scrutiny of clinical trials for prevention and treatment of various diseases. This has given rise to a pessimistic view of antioxidant therapy, however, the evidence from human epidemiological studies about the beneficial effects of dietary antioxidants and preclinical in vitro and animal data are compelling. We have probably wasted too much time on agents like antioxidant vitamins instead of focusing on more disease specific, target-directed, highly bioavailable antioxidants. We here discuss possible reasons for the lack of success in some clinical trials and seek to provide some suggestions to be considered if antioxidant therapy is to succeed as an effective therapeutic strategy.

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Section: Reactive Oxygen Species and Oxidative Stressmentioning

confidence: 99%

Section: Neurodegenerative Diseasesmentioning

confidence: 99%

Clinical and pharmacological aspects of bath salt use: A review of the literature and case reports

Miotto¹,

Striebel²,

Cho

et al. 2013

Drug and Alcohol Dependence

121

View full text Add to dashboard Cite

show abstract

“…Several studies have shown increased lipid peroxidation and DNA damage in transgenic mice expressing mutant SOD1 (an animal model for ALS) and in neural tissue or sera from ALS patients [55,56].…”

Section: Als and Lipid Peroxidationmentioning

confidence: 99%

Role Of Lipids In Brain Injury And Diseases

2007

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SummaryLipid metabolism is of particular interest due to its high concentration in CNS. The importance of lipids in cell signaling and tissue physiology is demonstrated by many CNS disorders and injuries that involve deregulated metabolism. The long suffering lipid field is gaining reputation and respect as evidenced through the Center of Biomedical Research Excellence in Lipidomics and Pathobiology (COBRE), Lipid MAPS (Metabolites And Pathways Strategy) Consortium sponsored by NIH, European initiatives for decoding the lipids through genomic approaches, and Genomics of Lipidassociated Disorder (GOLD) project initiated by Austrian government. This review attempts to provide an overview of the lipid imbalances associated with neurological disorders (Alzheimer's, Parkinson's; Niemann-Pick; Multiple sclerosis, Huntington, amyotrophic lateral sclerosis, schizophrenia, bipolar disorders and epilepsy) and CNS injury (Stroke, traumatic brain injury; and spinal cord injury) and a few provocative thoughts. Lipidomic analyses along with RNA silencing will provide new insights into the role of lipid intermediates in cell signaling and hopefully open new avenues for prevention or treatment options. KeywordsAlzheimer's disease; Arachidonic acid; CDP-choline; CNS injury; Docosahexaenoic acid; Huntington disease; Lipid peroxidation; Neurodegenerative diseases; Phospholipases; Phospholipids; Stroke Lipids and the Central Nervous System (CNS)Phospholipids are important components of all mammalian cells and have a variety of biological functions: 1) formation of lipid bilayers that provide structural integrity necessary for protein function 2) function as an energy reservoir (for example triglycerides) and 3) serve as precursors for various second messengers such as arachidonic acid (ArAc), docosahexaenoic acid (DHA), ceramide, 1,2-diacylglycerol (DAG), phosphatidic acid, and lyso-phosphatidic acid. Lipids comprise a large number of chemically distinct molecules arising from combinations of fatty acids with various backbone structures. Overall, mammalian cells may contain ~1000-2000 lipid species [1]. Lipids are classified into eight categories (fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterol lipids, prenol lipids, saccharolipids, and polyketides) [2]. Subtypes of these eight lipid classes are given in Table 1 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript metabolism may be of particular importance for the CNS, as this organ has a high concentration of lipids, second only to adipose tissue.Neurodegenerative diseases, mental disorders, stroke and CNS traumas are problems of vast clinical importance. Currently there exists no cure for these CNS injuries and disorders, resulting in a huge impact on quality of life and an economic burden on society (Table 2, based on the US population statistics). The crucial role of lipids in tissue physiology and cell signaling is demonstrated by the many neurological disorders, including bipolar disorders and schizophrenia, and neurodegenerative ...

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“…Evidence for oxidative damage to proteins and lipids has been detected in serum, fibroblasts, and the central nervous system (CNS) of ALS patients as well as various organs in the G93A mutant SOD1 transgenic murine model of ALS (13)(14)(15)(16)(17)(18)(19)(20). A central regulator of cellular responses to oxidative stress is the NRF2 (NF-E2-related factor 2)/KEAP1 (Kelch-like ECH-associated protein 1) pathway.…”

mentioning

confidence: 99%

RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1

Bakkar

Kousari

Kovalik

et al. 2015

Molecular and Cellular Biology

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons. Various factors contribute to the disease, including RNA binding protein dysregulation and oxidative stress, but their exact role in pathogenic mechanisms remains unclear. We have recently linked another RNA binding protein, RBM45, to ALS via increased levels of protein in the cerebrospinal fluid of ALS patients and its localization to cytoplasmic inclusions in ALS motor neurons. Here we show RBM45 nuclear exit in ALS spinal cord motor neurons compared to controls, a phenotype recapitulated in vitro in motor neurons treated with oxidative stressors. We find that RBM45 binds and stabilizes KEAP1, the inhibitor of the antioxidant response transcription factor NRF2. ALS lumbar spinal cord lysates similarly show increased cytoplasmic binding of KEAP1 and RBM45. Binding of RBM45 to KEAP1 impedes the protective antioxidant response, thus contributing to oxidative stress-induced cellular toxicity. Our findings thus describe a novel link between a mislocalized RNA binding protein implicated in ALS (RBM45) and dysregulation of the neuroprotective antioxidant response seen in the disease.A myotrophic lateral sclerosis (ALS) is a fatal idiopathic adultonset neurodegenerative disease characterized by a loss of motor neurons in the brain, brain stem, and spinal cord, with consequent atrophy of associated muscles (1, 2). Incidence rates are 1 to 3 cases per 100,000 individuals per year. Pathogenic mechanisms underlying the disease are not fully understood. Approximately 5 to 10% of all ALS cases are familial (3), with the remaining cases being termed sporadic, contributing to the clinical heterogeneity within the patient population. Nevertheless, typical hallmarks of ALS include neuronal atrophy, mitochondrial dysfunction, excitotoxicity, oxidative stress, and ubiquitinated cellular inclusions (4, 5). A growing number of genes with diverse functions have been implicated in the disease etiology. Mutations in a number of RNA binding proteins have been linked to ALS, including TAR DNA binding protein 43 (TDP-43) and Fused in Sarcoma (FUS) (6). Mutations in these genes result in reduced levels in the nucleus and their accumulation in cytoplasmic ubiquitin-positive inclusions (7). Both TDP-43 and FUS possess prion-like domains and relocate to cytoplasmic stress granules under stress conditions, suggesting potential pathology commonalities (8). Genetic alterations in these and other RNA binding proteins link RNA metabolism to the pathobiology of ALS.Recently, we linked another RNA binding protein, RBM45, to ALS using a proteomic screen of cerebrospinal fluid (CSF) from ALS and control subjects (9). RBM45, also known as Drb1, was first identified as a novel RNA binding protein that functions in neural development (10). RBM45 possesses three RNA recognition motifs (RRMs) as well as a C-terminal nuclear localization sequence (10). By using a large liquid chromatography-tandem mass spectrometry (LC-MS/MS) unbia...

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Increased lipid peroxidation in sera of ALS patients

Abstract: These data confirm the presence of increased oxidative stress and immune activation in ALS patients. HNE is also suggested as a possible biomarker of disease.

Cited by 291 publications

References 56 publications

Clinical and pharmacological aspects of bath salt use: A review of the literature and case reports

Clinical and pharmacological aspects of bath salt use: A review of the literature and case reports

Role Of Lipids In Brain Injury And Diseases

RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1

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