A Proposed Mechanism for Neurodegeneration in Movement Disorders Characterized by Metal Dyshomeostasis and Oxidative Stress  Benjamin Guy Trist, Dominic.

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A Proposed Mechanism for Neurodegeneration in Movement Disorders Characterized by Metal Dyshomeostasis and Oxidative Stress  Benjamin Guy Trist, Dominic James Hare, Kay Lorraine Double  Cell Chemical Biology  Volume 25, Issue 7, Pages 807-816 (July 2018) DOI: 10.1016/j.chembiol.2018.05.004 Copyright © 2018 Elsevier Ltd Terms and Conditions

Cell Chemical Biology 2018 25, 807-816DOI: (10. 1016/j. chembiol. 2018 Copyright © 2018 Elsevier Ltd Terms and Conditions

Figure 1 Structural Stability of SOD1 Protein Is Mediated by Specific Amino Acid Residues Crystal structure of the fully metallated dimeric SOD1 enzyme (A), depicted in ribbon (right hand monomer) and stick (left hand monomer) notation. The distribution of amino acid residues which are prone to oxidation (pink) (B), and which create the greatest destabilizing effect when oxidized, closely aligns with the dimer interface (red) and metal binding (orange and light blue) regions of SOD1 protein (A). Cell Chemical Biology 2018 25, 807-816DOI: (10.1016/j.chembiol.2018.05.004) Copyright © 2018 Elsevier Ltd Terms and Conditions

Figure 2 Normal and Pathological Biosynthesis of the SOD1 Enzyme (A) At base levels of oxidative stress within a neuron, continuous transcription of the sod1 gene creates a cycling pool of monomeric, metal-free (apo-mSOD1) protein, with unused enzyme metabolized by the 20S proteasome. When oxidative stress increases as a result of increased metabolic activity, cellular redox sensors induce additional protein transcription, stimulate loading of zinc(II) ions by way of an as-yet unknown mechanism, and initiate copper(II) loading and dimerization mediated by copper chaperone for SOD1 (CCS). During this process, formation of an intramolecular disulfide bridge between Cys57 and Cys146 encapsulates the copper ion and stabilizes the monomer, which dimerizes through hydrophobic interactions between Cys6, Cys111, and loops IV and IIV. The solvent-inaccessible space between the monomers forms an active dimer with high stability, which carries out its biological function and returns superoxide levels to baseline. (B) In conditions of elevated oxidative stress and copper dyshomeostasis, as experienced by dopaminergic neurons in PD and motor neurons in ALS, the ability of SOD1 to dimerize and perform its antioxidant role is impaired. A systemic decrease in bioavailable copper limits the maturation of SOD1, resulting in the accumulation of copper-deficient zinc-containing protein, which is notably more stable than apo-SOD1. The lack of antioxidant activity of this intermediate species leaves increasing levels of free radicals and reactive oxygen species unchecked. Without copper, SOD1 protein also possesses increased flexibility, exposing regions of the protein that are normally buried and solvent inaccessible to the harsh oxidative environment of degenerating regions. Among others, the four oxidation-prone cysteine residues in each monomer are likely exposed in this conformation, with thiols in Cys6 and Cys111 particularly prone to oxidative modification to sulfinic (-SO2H; shown here) and sulfonic (-SO3H) acids. Oxidative scrambling of Cys6 and Cys111 particularly promotes the formation of disordered oligomers, which eventually deposit as insoluble aggregates. These oligomers are implicated in mitochondrial dysfunction through interaction with the apoptosis regulator Bcl-2, further elevating levels of oxidative stress. The inability to mitigate increased oxidative activity in the PD brain can seed the formation of α-synuclein fibrils that precede Lewy body formation via post-translational modification of the peptide. The net effect of SOD1 dysfunction in both the PD and ALS CNS is a deficit in the endogenous response to high metabolic output and external stressors affecting oxidative load, leading to the eventual death of specific neuronal populations that impart a distinct disease phenotype. Cell Chemical Biology 2018 25, 807-816DOI: (10.1016/j.chembiol.2018.05.004) Copyright © 2018 Elsevier Ltd Terms and Conditions