Role of S-nitrosoglutathione and Hydrogen Peroxide on Cathepsin D Chemical Modification and Function

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by deposits of β-amyloid peptide (Aβ) and insoluble hyperphosphorylated Tau protein. Cathepsin D (CTSD) is the main lysosomal protease and it has been suggested as hyperphosphorylated Tau-degradating enzyme. Oxidants such as hydrogen peroxide (H2O2) and nitric oxide (NO) and its derivatives, S-nitrosoglutathione (GSNO) are greatly generated during altered states, such as AD. Oxidants can react with proteins causing post-translational modifications, such as S-nitrosylation and S-glutathionylation. Therefore, we hypothesize that oxidants generated during several stages of AD, cause post-translational modifications on CTSD, leading to its inactivation. In this study we utilized mouse brain homogenates treated with H2O2 or GSNO and oxidative modifications on CTSD were analyzed by Western blotting. Overall, our results demonstrate that CTSD is a target for oxidation, but surprisingly, neither oxidant robustly changed CTSD activity. As a conclusion this study suggests that, different from other proteases such as caspases, CTSD can sustain functionality in elevated oxidant conditions. The understanding of mechanisms by which oxidants can impair proteins involved in AD can provide knowledge for potential antioxidant therapies against neurodegenerative diseases, since these diseases have been associated with increases in oxidant production and damage.

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