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A Prion-like Mechanism in Amyotrophic Lateral Sclerosis

Explore the aggregation of SOD1 in ALS, elucidating oligomeric structures and molecular mechanisms through MD simulations and biochemical pathways. Investigate SOD1 misfolding, peroxidase functions, and regulation mechanisms in familial ALS.

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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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