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A Prion-like Mechanism in Amyotrophic Lateral Sclerosis

A Prion-like Mechanism in Amyotrophic Lateral Sclerosis. Dr. Eamonn F. Healy Professor of Chemistry St. Edward’s University Austin, Tx. familial ALS:the aggregation of wt and mutant SOD1. Prudencio, M. Et et al. Hum. Mol. Gen. 2010;19:4774-4789. Oligomeric structure of SOD1.

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A Prion-like Mechanism in Amyotrophic Lateral Sclerosis

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  1. A Prion-like Mechanism inAmyotrophic Lateral Sclerosis Dr. Eamonn F. Healy Professor of Chemistry St. Edward’s University Austin, Tx.

  2. familial ALS:the aggregation of wt and mutant SOD1 Prudencio, M. Et et al. Hum. Mol. Gen. 2010;19:4774-4789

  3. Oligomeric structure of SOD1 Biochem. Biophys. Res. Commun., 2015, 465 , 523-527.

  4. Aggregation of SOD1 Pathological Physiological Euro. Biophys. J., 2016, 45, 853-859.

  5. Frustration and enervation in SOD1 RMSF(Å)

  6. Schematic showing how MD simulations with the application of constraints used to simulate effects of SOD1 oligomerization. EL S S ZBL Chain F Chain A ZBL S S EL

  7. A unitary mechanism for propagated SOD1 misfolding

  8. SOD1 Function: dismutase mechanism Cu-His63=2.55 H TS 2 DG=2.4 DG=-11.5 H Pka(NH1)=14.5 H O O O- O O. DG#=17.6 DG#=-11.5 O H + O2-. + H+ Cu II Cu oxidation His deprotonation Cu II - H2O2 Cu I -His63 H-His63 H-His63 O. H TS 1 DG=1.0 O- O DG=7.8 O. DG#=12.6 DG=0 DG=0 Cu I + O2-. + H+ -O2 His protonation Cu II Cu I Cu II -His63 Cu reduction H-His63 -His63 DG#=31.4 H-His63 Pka=10.7 Cu-His63=3.1 Cu-Zn=6.6 Cu-Zn=6.1 Cu-His63=2.2 Cu-His63=2.31 Pelmenschikov , Inorg. Chem. (2005), 44, 3311 Red boxes denote metastable intermediates

  9. SOD1 Function: peroxidase mechanism Cu-His63=2.55 H TS 2 DG=2.4 DG=-11.5 H H O O O- O O. DG#=17.6 DG#=-11.5 O H + O2-. + H+ Cu II Cu oxidation His deprotonation Cu II - H2O2 Cu I -His63 H-His63 H-His63 O. H DG=1.0 TS 1 O- O DG=7.8 O. DG#=12.6 DG=0 DG=0 HO. H0- Cu I -O2 + H2O2 + O2-. + H+ Cu II Cu I Cu II -His63 His protonation Cu reduction H-His63 Cu II -His63 -His63 H-His63 Pka=10.7 Cu-His63=3.1 Cu-Zn=6.6 Cu-Zn=6.1 Cu-His63=2.2 Cu-His63=2.31 - O2-/ H+ . + H2O2

  10. CO2- DG=-32.6 H -0.20 -0.29 H2O CO3-. O O H-His61 Cu II -His61 Cu I Homolytic Cleavage DG=+1.6 CO2- H O O LUMO H-His61 H H Cu I -0.47 -0.27 O O H-His61 DG=-19.0 Cu I HO. H2O + H+ +CO2 Cu II -His61 Heterolytic Cleavage HOMO DG=+11.8 DG=+7 H - H H - H+ O O O O LUMO H H-His61 H H-His61 -0.38 Cu I O -0.36 Cu I O H-His61 Cu I DG=+11.3 H H + HO2- O O H-His61 Cu I + HCO4- HOMO + H2O2 H DG=+2.8 O H O. H DG=0 DG=-10.4 DG=- DG=-12.4 O O O- Cu I + H2O2 Cu II O - O2-. - H+ H Cu I -His61 H-His61 Cu II -His61 H-His61 Cu II H-His61

  11. End on binding of hydrogen peroxide His61 His46 His118 His44

  12. Regulation of activity through competitive inhibition

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