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Cited by 88Alzheimer's disease research and treatmentsProtein Kinase Regulation and GTPase SignalingNeuroscience and Neuropharmacology Research

Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery

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Wu, Xiaolei, Yang, Zhangzhong, Zou, Jinjun, Gao, Huile, Shao, Zhenhua, Li, Chuanzhou, Lei, Peng·2025·Signal Transduction and Targeted Therapy
DOI 10.1038/s41392-025-02179-xPMC PMC12056177
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Abstract

Neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s, Huntington’s disease, and Amyotrophic Lateral Sclerosis) are major health threats for the aging population and their prevalences continue to rise with the increasing of life expectancy. Although progress has been made, there is still a lack of effective cures to date, and an in-depth understanding of the molecular and cellular mechanisms of these neurodegenerative diseases is imperative for drug development. Protein phosphorylation, regulated by protein kinases and protein phosphatases, participates in most cellular events, whereas aberrant phosphorylation manifests as a main cause of diseases. As evidenced by pharmacological and pathological studies, protein kinases are proven to be promising therapeutic targets for various diseases, such as cancers, central nervous system disorders, and cardiovascular diseases. The mechanisms of protein phosphatases in pathophysiology have been extensively reviewed, but a systematic summary of the role of protein kinases in the nervous system is lacking. Here, we focus on the involvement of protein kinases in neurodegenerative diseases, by summarizing the current knowledge on the major kinases and related regulatory signal transduction pathways implicated in diseases. We further discuss the role and complexity of kinase–kinase networks in the pathogenesis of neurodegenerative diseases, illustrate the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies (such as antisense oligonucleotides and gene therapy) for effective prevention and early intervention.

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  • Mitochondrial oxidative stress activates GSK3β and CDK5, promoting tau hyperphosphorylation.

    “Mechanistically, abnormal localization of APP to mitochondria-associated membranes alters γ-secretase function and enhances Aβ generation [61], while mitochondrial oxidative stress activates kinases such as GSK3β and CDK5, promoting tau hyperphosphorylation [62].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [62]

    In the AD section (GSK3β and CDK5 subsections; page unavailable), the paper says these kinases promote tau phosphorylation, including hyperphosphorylation. Figure 5 also describes oxidative stress as a condition that can lead to CDK5 overactivation. The cited passages do not establish the more specific claim that mitochondrial oxidative stress activates both CDK5 and GSK3β; the AD section instead describes GSK3β activity and CDK5 dysfunction as contributing to oxidative stress or mitochondrial dysfunction. (LLM, conf=0.87)

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Cited by

Sorted by citations

Authors
Wu, X., Yang, Z., Zou, J., Gao, H., Shao, Z., Li, C., & Lei, P.
Affiliations
  • Sichuan University (CN)
  • Huazhong University of Science and Technology (CN)
Corresponding author
  • Li, Chuanzhou
  • Lei, Peng
ORCID
Venue
Signal Transduction and Targeted Therapy
Publisher
Springer Science and Business Media LLC
Published
2025-05-07
Volume
10
Issue
1
Pages
146-146
ISSN
2059-3635 (ISSN-L)
DOI
10.1038/s41392-025-02179-x
PMC
PMC12056177
OpenAlex
W4410109090
Cited by
88
References
42
Citations by year
2026: 68 · 2025: 20
FWCI
10.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (32070961, 2023ZD0507200)
  • Sichuan University
  • National Science and Technology Major Project (2023ZD0507200)
  • Natural Science Foundation of Sichuan Province
  • West China Hospital, Sichuan University
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
protein kinases, neurodegenerative diseases, protein phosphorylation, protein phosphatase, signaling pathways, kinase inhibitors, antisense oligonucleotides, gene therapy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, drug discovery
MeSH terms
Animals, Humans, Phosphorylation, Protein Kinases, Signal Transduction, Neurodegenerative Diseases, Protein Kinase Inhibitors, Drug Discovery

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