Cdk5, an atypical cyclin-dependent kinase, is a proline-directed serine/threonine protein kinase. It is highly expressed in post-mitotic neurons and 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 cell cycle-related processes, apoptosis, and cell survival, and plays a role in multiple pathways including those related to neurodegeneration, cancer progression, and immune evasion [3,4].

Specifically, abrogating Cdk5 activity during mitosis leads to mitotic defects, nuclear atypia, and changes in the mitotic phosphoproteome, indicating its role in maintaining mitotic fidelity as a partner of cyclin B1 [1]. In neurodegenerative diseases like Alzheimer's disease (AD), its dysregulation, such as aberrant hyperactivation, is observed, and it interacts with AD-related proteins like amyloid-beta precursor protein (APP) and tau protein, influencing disease progression [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 normal cellular functions, especially in neurons. Studies using models that disrupt Cdk5 function, like those abrogating its activity during mitosis or in disease-related contexts, have revealed its significance in mitotic fidelity, neurodegeneration, and cancer-related immune evasion. Understanding Cdk5's functions through these model-based studies provides insights into the mechanisms of these biological processes and diseases, potentially guiding future therapeutic strategies.