Chemical Knockdown of Phosphorylated p38 Mitogen-Activated Protein Kinase (MAPK) as a Novel Approach for the Treatment of Alzheimer ' s Diseaseopen access
- Authors
- Son, Seung Hwan; Lee, Na-Rae; Gee, Min Sung; Song, Chae Won; Lee, Soo Jin; Lee, Sang-Kyung; Lee, Yoonji; Kim, Hee Jin; Lee, Jong Kil; Inn, Kyung-Soo; Kim, Nam-Jung
- Issue Date
- Mar-2023
- Publisher
- AMER CHEMICAL SOC
- Citation
- ACS CENTRAL SCIENCE, v.9, no.3, pp.417 - 426
- Indexed
- SCIE
SCOPUS
- Journal Title
- ACS CENTRAL SCIENCE
- Volume
- 9
- Number
- 3
- Start Page
- 417
- End Page
- 426
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/184897
- DOI
- 10.1021/acscentsci.2c01369
- ISSN
- 2374-7943
- Abstract
- 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-depend-ent 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 (A beta) 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.
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