Journal Article

Chemical Knockdown of Phosphorylated p38 Mitogen-Activated Protein Kinase (MAPK) as a Novel Approach for the Treatment of Alzheimer′s Disease

Song, Chae Won, Lee, Jong Kil, Lee, Sang-Kyung, Lee, Soo Jin, Gee, Min Sung, Kim, Nam-Jung, Kim, Hee Jin, Lee, Na-Rae, Lee, Yoonji, Son, Seung Hwan, Inn, Kyung-Soo

2023

Overview

Targeted protein degradation (TPD) provides unique advantages over gene knockdown in that it can induce selective degradation of disease-associated proteins attributed to pathological mutations or aberrant post-translational modifications (PTMs). Herein, we report a protein degrader, PRZ-18002, that selectively binds to an active form of p38 MAPK. PRZ-18002 induces degradation of phosphorylated p38 MAPK (p-p38) and a phosphomimetic mutant of p38 MAPK in a proteasome-dependent manner. Given that the activation of p38 MAPK plays pivotal roles in the pathophysiology of Alzheimer’s disease (AD), selective degradation of p-p38 may provide an attractive therapeutic option for the treatment of AD. In the 5xFAD transgenic mice model of AD, intranasal treatment of PRZ-18002 reduces p-p38 levels and alleviates microglia activation and amyloid beta (Aβ) deposition, leading to subsequent improvement of spatial learning and memory. Collectively, our findings suggest that PRZ-18002 ameliorates AD pathophysiology via selective degradation of p-p38, highlighting a novel therapeutic TPD modality that targets a specific PTM to induce selective degradation of neurodegenerative disease-associated protein.

• Publisher: American Chemical Society
• Subject: Alzheimer's disease / Biodegradation / Degradation / Kinases / Ligands / MAP kinase / Microglia / Neurodegenerative diseases / Pathophysiology / Phosphorylation / Post-translation / Proteasomes / Proteins / Signal transduction / Spatial discrimination learning / Spatial memory / Transgenic mice / β-Amyloid