Cdk5, an atypical cyclin-dependent kinase, is a proline-directed serine/threonine protein kinase. It is highly expressed in post-mitotic neurons and is activated by non-cyclin proteins p35 and p39. Cdk5 governs various cellular processes in neurons, and its dysregulation can compromise normal brain function. It is also involved in pathways related to cell cycle, apoptosis, and immune response, and has significance in many physiological and pathological conditions [3,4,6]. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions.

Specifically, in mitosis, abrogating Cdk5 activity leads to mitotic defects, nuclear atypia, and changes in the mitotic phosphoproteome, indicating its role in maintaining mitotic fidelity as a partner with cyclin B1 [1]. In neurodegenerative diseases like Alzheimer's, its dysregulation, including aberrant hyperactivation, impacts disease progression through interactions with proteins like amyloid-beta precursor protein and tau [5]. In breast cancer brain metastasis, astrocyte-induced Cdk5 overexpression helps cancer cells evade immune recognition by suppressing MHC-I expression, and inhibiting Cdk5 can enhance the efficacy of immune checkpoint inhibitors [2].

In conclusion, Cdk5 is crucial for maintaining mitotic fidelity, has a significant impact on neurodegenerative diseases, and plays a role in cancer immune evasion. Model-based research, especially KO/CKO mouse models, has provided insights into its functions in these disease areas, helping us better understand the underlying mechanisms and potentially develop new therapeutic strategies.

References:

1. Zheng, Xiao-Feng, Sarkar, Aniruddha, Lotana, Humphrey, Spektor, Alexander, Chowdhury, Dipanjan. 2024. CDK5-cyclin B1 regulates mitotic fidelity. In Nature, 633, 932-940. doi:10.1038/s41586-024-07888-x. https://pubmed.ncbi.nlm.nih.gov/39232161/

2. Yuzhalin, Arseniy E, Lowery, Frank J, Saito, Yohei, Hung, Mien-Chie, Yu, Dihua. 2024. Astrocyte-induced Cdk5 expedites breast cancer brain metastasis by suppressing MHC-I expression to evade immune recognition. In Nature cell biology, 26, 1773-1789. doi:10.1038/s41556-024-01509-5. https://pubmed.ncbi.nlm.nih.gov/39304713/

3. Pao, Ping-Chieh, Tsai, Li-Huei. 2021. Three decades of Cdk5. In Journal of biomedical science, 28, 79. doi:10.1186/s12929-021-00774-y. https://pubmed.ncbi.nlm.nih.gov/34814918/

4. Roufayel, Rabih, Murshid, Nimer. 2019. CDK5: Key Regulator of Apoptosis and Cell Survival. In Biomedicines, 7, . doi:10.3390/biomedicines7040088. https://pubmed.ncbi.nlm.nih.gov/31698798/

5. Garemilla, Sandilya, Kumari, Richa, Kumar, Rahul. 2024. CDK5 as a therapeutic tool for the treatment of Alzheimer's disease: A review. In European journal of pharmacology, 978, 176760. doi:10.1016/j.ejphar.2024.176760. https://pubmed.ncbi.nlm.nih.gov/38901526/

6. Wang, Jiahui, Zhang, Chong, Jiang, Tingting, Yan, Jianguo, Zhou, Yali. 2025. CDK5: Insights into its roles in diseases. In Molecular biology reports, 52, 145. doi:10.1007/s11033-025-10253-4. https://pubmed.ncbi.nlm.nih.gov/39836243/