Superoxide Dismutase 1 Oxidation as a Mechanism of Cell Death in Amyotrophic Lateral Sclerosis

Superoxide Dismutase 1 Oxidation as a Mechanism of Cell Death in Amyotrophic Lateral Sclerosis
Author: Leilanie Clayton
Publisher:
Total Pages: 182
Release: 2010
Genre:
ISBN:

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, is an adult-onset, progressive and fatal neurodegenerative disease. Pathologically, it is characterized by a loss of motor neurons in the spinal cord, brain stem and motor cortex leading to progressive muscle weakness, atrophy, and death. ALS presents as both a sporadic (SALS) and familial (FALS) illness. Interestingly, over 100 mutations of the CuZn-Superoxide Dismutase (SOD1) gene have been reported to be dominantly inherited in ALS families. SOD1 is a 17KD protein that contains one copper and one zinc atom. The known function of this enzyme is to convert superoxide to oxygen and hydrogen peroxide. It was first thought that the toxicity of different SOD1 mutants linked to ALS resulted from decreased free-radical scavenging activity. However, studies show that mutant SOD1 enzymes cause motor neuron degeneration via a gain of harmful properties. The nature of the gain-of-toxic function in mutant SOD1 is not clear. Recent studies suggest that SOD1 itself is a target of oxidative stress. Human SOD1 has four cysteine residues, Cys6, Cys57, Cys111, and Cys146. An internal disulfide bond exists between Cys57 and Cys146. This disulfide bond is highly conserved in SOD1, making the protein considerably strong, while the remaining two cysteine residues are free and prone to post-translational modifications. Here we show that free cysteine residues in SOD1 are available to be modified by mal PEG (Maleimide polyethylene glycol) and AMS, and that this modification decreases with disease progression. Our data suggests that cysteine residues in SOD1 are post-translationally modified and may play a significant role in the development of the disease.

Metal Ions and Neurodegenerative Disorders

Metal Ions and Neurodegenerative Disorders
Author: Paolo Zatta
Publisher: World Scientific
Total Pages: 546
Release: 2003
Genre: Medical
ISBN: 9789812796691

Numerous studies have established a clear connection between neuronal oxidative stress and several neurodegenerative diseases, with consequential damages to lipids, proteins, nucleic acids, etc. In addition, several modifications indicative of oxidative stress have been described in association with neurons, neurofibrillary tangles and senile plaques in Alzheimer''s disease, including advanced glycation end products and free carbonyl oxidation. Oxidative damage and antioxidant responses are now well characterized, but sources of damaging free radicals are yet to be fully understood. Evidences of alteration in metal ions metabolism have been reported in various diseases like Alzheimer''s, Wilson, Menkes, Prion, Pick, Huntington disease, epilepsy and other pathological events. Thus, metal ions play a pivotal role in neurodegenerative phenomena. Chelation therapy is still in the early days of its development, but research in this area could lead to new products that could revolutionize treatment. Two international conferences on OC Metals and the Brain: From Neurochemistry to NeurodegenerationOCO (Padova, Italy, 2000 and Fez, Morocco, 2002) were recently held to discuss the role of metal ions in neurophysiopathology. A third will be held in 2005 in Johannesburg, South Africa. This book follows the same train of thought as those conferences, in order to highlight the unquestionable importance of metal ions in the research on the neurophysiopathology of neurodegenerative diseases. The excellent reputation of the scientists who have contributed to this project ensures the quality of the chapters presented here, and hopefully this will help spur new research initiatives in the field, which is still in its infancy. Contents: Metal-Catalyzed Redox Activity in Neurodegenerative Disease (M A Taddeo et al.); Aluminum and Central Nervous System Morphology in Hemodialysis (E Reusche); Transition Metals, Oxidation, Lipoproteins, and Amyloid-: Major Players in Alzheimer''s Disease (A Kontush); Molecular Basis of Copper Transport: Cellular and Physiological Functions of Menkes and Wilson Disease Proteins (ATP7A and ATP7B) (D R Kramer et al.); Copper-Zinc Superoxide Dismutase and Familial Amyotrophic Lateral Sclerosis (M B Yim et al.); Copper and Prion Disease (J Sasson & D Brown); Metallothioneins in Neurodegeneration (M Aschner et al.); Iron and Neurodegeneration (S L Grab & J R Connor); Iron, Neuromelanin, and -Synuclein in Neuropathogenesis of Parkinson''s Disease (K L Double et al.); Iron and Epilepsy (W-Y Ong et al.); Role of Iron Metabolism in Multiple Sclerosis (M J Kotze et al.); Neuroprotective Effects of Lithium (S Ermidiou-Pollet & S Pollet); and other articles. Readership: Academics, graduate students and researchers in neurology, psychiatry, neuroscience and environmental health."