Copper Zinc Superoxide Dismutase And Amyotrophic Lateral Sclerosis
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Copper, Zinc Superoxide Dismutase Misfolding in Amyotrophic Lateral Sclerosis
Author | : Rishi Rakhit |
Publisher | : |
Total Pages | : 494 |
Release | : 2009 |
Genre | : |
ISBN | : 9780494591352 |
Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration resulting in progressive paralysis and death. The only known cause of typical ALS is mutations in SOD1; these predominantly missense mutations produce a toxic gain-of-function in the enzyme Cu/Zn superoxide dismutase (SOD1). The prevailing hypotheses regarding the mechanism of toxicity were (a) oxidative damage from aberrant SOD1 redox chemistry, and (b) misfolding of the mutant protein. The goal of this thesis was to investigate the molecular mechanisms of the mutant SOD1 (mSOD1) misfolding and toxicity.To interrogate the in vivo misfolding pathway of SOD1, we used its high-resolution structure to create an antibody that reacts with monomer/misfolded SOD1 but not the native dimer. Upon verifying the reactivity of this antibody, we showed that monomer/misfolded SOD1 is found in a human case of familial ALS and in transgenic animal models of ALS. Misfolded SOD1 is found primarily in affected cells, motor neurons. Misfolded SOD1 is also initially absent, but appears prior to symptom onset. These observations together suggest a causal role for SOD1 misfolding through a monomeric intermediate in ALS pathogenesis.Because oxidation of SOD1 primarily affected the metal-binding His residues, we hypothesized that oxidation of wild-type, holo-SOD1 should lead to aggregation. Increasing the concentration of wild-type SOD1 in oxidation reactions produced aggregates similar to those observed earlier. Both wild-type and mSOD1 aggregation kinetics revealed an initial decrease in particle size rather than a monotonic increase using dynamic light scattering. This was consistent with the conversion of SOD1, normally an obligate homodimer, into monomers prior to aggregation. This observation was confirmed using analyatical ultracentrifugation. The common aggregation pathway for wild-type and mSOD1 suggested a mechanism for sporadic ALS caused by SOD1 misfolding.We proposed that oxidative damage to SOD1 itself could cause its misfolding and aggregation. To investigate this hypothesis, we subjected purified SOD1 in vitro to metal catalyzed oxidation. Oxidation of SOD1 produced aggregates reminiscent of those observed in ALS pathology. Aggregation propensity of zinc-deficient SOD1 and several mSOD1s known to have lower zinc-binding affinity was proportional to partial unfolding. Oxidation of SOD1 caused conversion of several His residues to 2-oxo-histidine.
Gain of Toxic Properties of Amyotrophic Lateral Sclerosis-causing Copper/zinc Superoxide Dismutase Variants
Author | : Qi Wang |
Publisher | : |
Total Pages | : 196 |
Release | : 2010 |
Genre | : Superoxide dismutase |
ISBN | : |