PLK1 (Polo-Like Kinase 1) is a serine/threonine protein kinase that functions as a master regulator of mitosis. The PLK1 protein is encoded by the PLK1 gene located on chromosome 16p12.2 and consists of 603 amino acids with a conserved kinase domain and polo-box domains that mediate protein-protein interactions[1].
PLK1 is essential for multiple aspects of cell division, including centrosome maturation, spindle assembly, chromosome segregation, and cytokinesis. Its activity is tightly regulated across the cell cycle, with peak activity during mitosis. While PLK1 is primarily studied in the context of cancer and cell proliferation, emerging evidence links PLK1 dysregulation to neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.
The unexpected finding that PLK1 is expressed in post-mitotic neurons and functions in synaptic plasticity, axonal repair, and DNA damage response has opened new research avenues for understanding PLK1's role in neurodegeneration.
The PLK1 protein contains several distinct functional domains that mediate its diverse cellular functions. The N-terminal kinase domain (~250 amino acids) contains the catalytic activity responsible for phosphorylating substrate proteins. This domain shares homology with other polo-like kinases and the AKT/PKB family[2].
The C-terminal polo-box domain (PBD) consists of two polo-box motifs that mediate protein-protein interactions. The PBD recognizes phospho-Ser/Thr-Pro motifs in target proteins, enabling PLK1 to bind specific substrates. This domain is essential for:
PLK1 also contains a polo-box interacting region (PBI) that allows intramolecular regulation. The kinase domain and PBD interact in an auto-inhibitory conformation in interphase, with this inhibition releasing during mitosis.
PLK1 activity is regulated at multiple levels:
Transcriptional regulation:
Post-translational regulation:
Subcellular localization:
This dynamic localization allows PLK1 to function at different mitotic structures, coordinating the progression of cell division.
PLK1 phosphorylates numerous substrates involved in mitosis. Key substrates include[1:1]:
The recognition motif for PLK1 phosphorylation is typically (Ser/Thr)-Pro, with prior phosphorylation by other kinases often required for PLK1 recognition.
At mitotic entry, PLK1 is recruited to centrosomes, where it promotes centrosome maturation—the process by which centrosomes acquire the ability to nucleate microtubules[3]. PLK1 phosphorylates several centrosomal proteins:
This function is essential for forming functional spindle poles and ensuring proper chromosome segregation.
PLK1 contributes to spindle assembly through multiple mechanisms[4]:
The PLK1-dependent phosphorylation network ensures proper spindle formation and attachment of kinetochores to spindle microtubules.
During metaphase and anaphase, PLK1 localizes to kinetochores and the spindle midzone. Its functions include[4:1]:
PLK1 inhibition causes mitotic arrest with misalignment of chromosomes and failed spindle checkpoint satisfaction.
PLK1 is essential for cytokinesis, the final step of cell division[5]. It localizes to the spindle midzone and the contractile ring, where it:
PLK1 dysfunction leads to cytokinesis failure, multinucleation, and potential polyploidy.
Despite being a mitotic regulator, PLK1 is expressed in post-mitotic neurons. Its expression in neurons is lower than in proliferating cells but is detectable in various brain regions, including the hippocampus, cortex, and cerebellum.
Neuronal PLK1 expression serves different functions than in dividing cells:
Synaptic functions:
Axonal functions:
DNA damage response:
PLK1 has unexpected roles in synaptic plasticity. At synapses, PLK1 phosphorylates proteins involved in[6]:
These phosphorylation events modulate synaptic strength and plasticity. PLK1 activity at synapses is regulated by neuronal activity, suggesting it participates in activity-dependent synaptic modifications.
After neuronal injury, PLK1 plays a positive role in axonal regeneration[7]. PLK1:
This function suggests PLK1 activation could potentially promote nerve repair after injury or in neurodegenerative conditions.
Alzheimer's disease is associated with inappropriate reactivation of cell cycle proteins in post-mitotic neurons. PLK1 expression is altered in AD brains, with some studies showing upregulation[8].
The dysregulation of PLK1 in AD may contribute to:
This phenomenon of "mitotic catastrophe" represents a failed attempt by neurons to re-enter the cell cycle, leading to cell death rather than division.
PLK1 phosphorylates tau protein at multiple sites relevant to Alzheimer's disease pathology[9]. PLK1-mediated tau phosphorylation:
The intersection between PLK1 and tau pathology makes PLK1 a potential therapeutic target for AD. Inhibiting PLK1 could reduce tau phosphorylation and aggregation.
Targeting PLK1 in AD presents challenges due to its dual roles:
The therapeutic approach may need to be context-specific, considering disease stage and specific pathological features.
In Parkinson's disease, dopaminergic neurons in the substantia nigra are particularly vulnerable. PLK1 dysregulation may contribute to this vulnerability[10].
Changes in PLK1 in PD include:
PLK1 may interact with α-synuclein metabolism, the protein that forms Lewy bodies in PD:
Given PLK1's role in axonal regeneration, enhancing PLK1 function could potentially promote recovery in PD. However, this must be balanced against potential negative effects on cell cycle regulation.
PLK1 participates in the DNA damage response, a function particularly relevant to neurons that accumulate DNA damage with aging and in neurodegeneration[11].
PLK1 functions in DNA damage response include:
The DNA damage response functions of PLK1 may be protective in neurons:
However, dysregulated PLK1 could lead to inappropriate cell cycle reentry following DNA damage.
PLK1 is a validated therapeutic target in cancer. Several PLK1 inhibitors have been developed and tested in clinical trials[12]:
These inhibitors cause mitotic arrest and cell death in proliferating cancer cells.
The use of PLK1 inhibitors in neurodegeneration requires careful consideration:
Potential benefits:
Concerns:
The therapeutic window may depend on specific disease contexts and dosing strategies.
Approaches to selectively modulate PLK1 in the nervous system include:
PLK1 functions in mitosis and beyond. Journal of Cell Science. 2012. ↩︎ ↩︎
Polo-like kinases in cell cycle regulation. Nature Reviews Molecular Cell Biology. 2014. ↩︎
PLK1-mediated centrosome maturation in cell division. Developmental Cell. 2011. ↩︎
PLK1 in spindle assembly and chromosome segregation. Cell Cycle. 2013. ↩︎ ↩︎
PLK1 in cytokinesis and abscission. Current Biology. 2012. ↩︎
PLK1 functions at the synapse: unexpected roles. Synapse. 2019. ↩︎
PLK1 in axonal regeneration and neuronal repair. Journal of Neuroscience. 2020. ↩︎
Polo-like kinase 1 in Alzheimer's disease pathology. Acta Neuropathologica. 2020. ↩︎
PLK1-mediated tau phosphorylation in Alzheimer's disease. Journal of Biological Chemistry. 2019. ↩︎
PLK1 dysregulation in Parkinson's disease models. Molecular Neurobiology. 2021. ↩︎
PLK1 in DNA damage response and repair. DNA Repair. 2020. ↩︎
Polo-like kinase inhibitors in clinical development. Journal of Medicinal Chemistry. 2021. ↩︎