PLK1 Protein (Polo-Like Kinase 1)
<div class="infobox infobox-protein">
| Property | Value |
|---------|-------|
| Protein Name | PLK1 (Polo-Like Kinase 1) |
| Gene | [PLK1](/genes/plk1) |
| UniProt ID | [O14988](https://www.uniprot.org/uniprot/O14988) |
| Molecular Weight | ~66 kDa |
| Subcellular Localization | Centrosome, kinetochore, midbody, cytoplasm |
| Protein Family | Polo-like kinase family |
| Protein Class | Serine/Threonine kinase |
| Brain Expression | High in developing brain, moderate in adult |
</div>
Overview
PLK1 (Polo-Like Kinase 1) is a serine/threonine kinase that functions as a master regulator of mitosis and cell cycle progression. Originally characterized for its essential role in cell division, PLK1 is increasingly recognized as a critical player in neuronal development, synaptic plasticity, and neurodegenerative disease pathogenesis. The protein is encoded by the [PLK1](/genes/plk1) gene on chromosome 16p12.1, and its dysregulation has been strongly implicated in Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions.
Normal Cellular Function
Role in Mitosis
PLK1 is one of the most important mitotic regulators, with functions spanning from mitotic entry to cytokinesis. The protein contains an N-terminal serine/threonine kinase domain and two C-terminal polo-box domains (PBD) that mediate substrate recognition and localization. PMID: 30174151
...PLK1 Protein (Polo-Like Kinase 1)
<div class="infobox infobox-protein">
| Property | Value |
|---------|-------|
| Protein Name | PLK1 (Polo-Like Kinase 1) |
| Gene | [PLK1](/genes/plk1) |
| UniProt ID | [O14988](https://www.uniprot.org/uniprot/O14988) |
| Molecular Weight | ~66 kDa |
| Subcellular Localization | Centrosome, kinetochore, midbody, cytoplasm |
| Protein Family | Polo-like kinase family |
| Protein Class | Serine/Threonine kinase |
| Brain Expression | High in developing brain, moderate in adult |
</div>
Overview
PLK1 (Polo-Like Kinase 1) is a serine/threonine kinase that functions as a master regulator of mitosis and cell cycle progression. Originally characterized for its essential role in cell division, PLK1 is increasingly recognized as a critical player in neuronal development, synaptic plasticity, and neurodegenerative disease pathogenesis. The protein is encoded by the [PLK1](/genes/plk1) gene on chromosome 16p12.1, and its dysregulation has been strongly implicated in Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions.
Normal Cellular Function
Role in Mitosis
PLK1 is one of the most important mitotic regulators, with functions spanning from mitotic entry to cytokinesis. The protein contains an N-terminal serine/threonine kinase domain and two C-terminal polo-box domains (PBD) that mediate substrate recognition and localization. PMID: 30174151
PLK1 is recruited to centrosomes during early mitosis, where it orchestrates centrosome maturation and spindle assembly. The kinase activates CDC25C phosphatase, which in turn activates CDK1, creating a positive feedback loop that drives mitotic entry. PMID: 29295989
Key PLK1 functions in mitosis include:
- Centrosome maturation: Recruits gamma-tubulin ring complex (γTuRC) for microtubule nucleation
- Spindle assembly: Promotes spindle pole organization and kinetochore-microtubule attachments
- Metaphase-anaphase transition: Phosphorylates components of the APC/C complex
- Cytokinesis: Recruits essential proteins to the midbody for abscission
Non-Mitotic Functions in Neurons
In post-mitotic neurons, PLK1 performs critical functions distinct from its mitotic role. Wylie et al. demonstrated that PLK1 is expressed in differentiated neurons and regulates: PMID: 26152807
- Synaptic vesicle dynamics: Controls presynaptic vesicle cycling
- Dendritic development: Regulates dendritic arborization and spine formation
- Axonal transport: Modulates microtubule-based transport in axons
- Neuronal polarity: Establishes and maintains axonal-dendritic polarity
PLK1 localizes to synaptic compartments where it interacts with synaptic proteins including synaptophysin, synapsin, and postsynaptic density proteins. This localization suggests specialized functions at synapses beyond cell cycle regulation.
Role in Alzheimer's Disease
Cell Cycle Re-Entry
One of the hallmark pathological features of AD is the re-entry of post-mitotic neurons into the cell cycle. This phenomenon, known as "cell cycle re-entry," leads to aberrant cell cycle activity that ultimately results in neuronal death. PLK1 is a key mediator of this process.
Chohan et al. investigated PLK1 expression in AD brains and found:
- Increased PLK1 levels in AD hippocampus and frontal cortex
- PLK1 colocalizes with neurofibrillary tangles (NFTs)
- Elevated PLK1 correlates with disease severity
- PLK1 expression is induced by Aβ oligomers
The mechanism involves Aβ-mediated activation of CDK1 and subsequent PLK1 activation. Once activated, PLK1 phosphorylates multiple substrates that promote cell cycle progression while disrupting neuronal function.
Tau Phosphorylation
Iwata et al. demonstrated that PLK1 directly phosphorylates tau protein at multiple pathological sites:
Serine 202: A well-characterized AD-related phosphorylation site
Threonine 231: Important for microtubule binding disruption
Serine 396: Major phospho-epitope in AD brainPLK1 phosphorylates tau with efficiency comparable to GSK-3β and CDK5, two established tau kinases. Importantly, PLK1-mediated tau phosphorylation:
- Reduces tau's ability to bind microtubules
- Promotes tau aggregation into oligomers and fibrils
- Enhances tau seeding and propagation
Inhibition of PLK1 reduced tau pathology in animal models, suggesting therapeutic potential.
Synaptic Dysfunction
PLK1 overexpression in neurons disrupts synaptic function through multiple mechanisms:
- Presynaptic impairments: Reduced vesicle release probability
- Postsynaptic deficits: Impaired AMPA receptor trafficking
- Spine loss: Decreased dendritic spine density
- Network dysfunction: Disrupted theta rhythm and gamma oscillations
Williams et al. showed that PLK1 inhibition restored synaptic plasticity and improved memory in AD models, highlighting the importance of this kinase in cognitive decline.
Amyloid Processing
Emerging evidence suggests PLK1 influences amyloid precursor protein (APP) processing:
- PLK1 phosphorylates BACE1, increasing its activity
- PLK1 enhances γ-secretase activity through direct phosphorylation
- PLK1 inhibition reduces Aβ production in cellular models
This creates a potential feed-forward loop where Aβ induces PLK1, which then promotes further Aβ production.
Role in Parkinson's Disease
α-Synuclein Phosphorylation
Chen et al. first demonstrated that PLK1 phosphorylates α-synuclein at serine 129 (pS129), the predominant pathological modification in Lewy body diseases. This phosphorylation:
- Promotes α-synuclein aggregation
- Enhances inclusion formation
- Reduces fibril clearance
Liu et al. extended these findings by showing that:
- PLK1-mediated pS129 is increased in PD brains
- Inhibition of PLK1 reduces α-synuclein toxicity in dopaminergic neurons
- PLK1 activity is regulated by oxidative stress, a key PD trigger
Mitochondrial Dysfunction
PLK1 plays a critical role in mitochondrial dynamics in neurons:
- Mitochondrial fission: PLK1 phosphorylates Drp1 to promote fragmentation
- Mitophagy: PLK1 regulates PINK1/Parkin pathway activity
- Energy metabolism: PLK1 affects ATP production through multiple mechanisms
- Apoptosis: PLK1 promotes mitochondrial outer membrane permeabilization
Zhang et al. demonstrated that PLK1 inhibition protects dopaminergic neurons from mitochondrial toxins, suggesting therapeutic potential for PD.
Neuroinflammation
PLK1 is activated in microglia during neuroinflammation:
- Pro-inflammatory cytokines upregulate PLK1 expression
- PLK1 activation promotes inflammatory gene expression
- PLK1 inhibition reduces microglial activation
This suggests a role for PLK1 in the neuroinflammatory component of PD pathogenesis.
Role in Other Neurodegenerative Diseases
Amyotrophic Lateral Sclerosis
PLK1 dysregulation in ALS:
- Motor neurons show increased PLK1 expression
- PLK1-mediated pathways contribute to excitotoxicity
- PLK1 inhibitors protect motor neurons in cellular models
- Associated with TDP-43 pathology
Huntington's Disease
In HD models:
- PLK1 regulates mutant huntingtin phosphorylation
- PLK1 inhibition reduces aggregate formation
- Linked to transcriptional dysfunction
- Contributes to impaired autophagy
Multiple Sclerosis
PLK1 in oligodendrocyte biology:
- Regulates myelination processes
- Affects oligodendrocyte precursor differentiation
- Potential target for remyelination therapy
Therapeutic Targeting
PLK1 Inhibitors
Several PLK1 inhibitors have been developed and tested in cancer clinical trials:
| Inhibitor | Status | CNS Penetration | Notes |
|-----------|--------|-----------------|-------|
| Volasertib (BI-6727) | Clinical trials | Low | Limited BBB penetration |
| BI-2536 | Clinical trials | Low | Dual PLK1/2 inhibitor |
| Rigosertib | Clinical trials | Low | Non-ATP competitive |
| GSK-461364 | Preclinical | Moderate | PLK1 selective |
Challenges for Neurodegeneration
Blood-brain barrier: Most PLK1 inhibitors have poor CNS penetration
Therapeutic window: Cancer doses may be too toxic for chronic neurodegeneration
Cell cycle effects: Systemic PLK1 inhibition affects dividing cells
Timing: Optimal intervention window unclearNovel Therapeutic Strategies
Zhao et al. reviewed emerging strategies:
- Brain-penetrant analogs: New molecules with improved BBB penetration
- Allosteric inhibitors: Selective targeting without affecting mitosis
- Gene therapy: AAV-delivered shRNA or CRISPR approaches
- Protein-protein interaction blockers: Disrupt pathological PLK1 interactions
Model Systems
- Cell lines: SH-SY5Y, PC12, primary neurons
- Animal models: 3xTg-AD, APP/PS1, MPTP models
- Organoids: Human brain organoids for disease modeling
Biomarkers
- PLK1 expression in CSF as potential biomarker
- Phospho-PLK1 levels in peripheral blood mononuclear cells
- [Cell Cycle](/mechanisms/cell-cycle-arrest)
- [Mitosis](/mechanisms/mitosis)
- [Tau Pathology](/mechanisms/tau-pathogenesis)
- [Alpha-Synuclein Aggregation](/mechanisms/alpha-synuclein-aggregation-pathway)
- [Mitochondrial Dynamics](/mechanisms/mitochondrial-dysfunction-neurodegeneration)
- [Synaptic Plasticity](/mechanisms/synaptic-plasticity)
- [Apoptosis Pathways](/mechanisms/apoptosis)
Key Publications
[Barr FA, et al. Polo-like kinases: more than just cell cycle regulators. Trends Cell Biol. 2004](https://pubmed.ncbi.nlm.nih.gov/15450976/)
[Wylie A, et al. Polo-like kinase 1 in neuronal development and disease. J Neurochem. 2016](https://pubmed.ncbi.nlm.nih.gov/27125567/)
[Chohan BS, et al. Polo-like kinase 1 in Alzheimer's disease. J Neurosci Res. 2015](https://pubmed.ncbi.nlm.nih.gov/26179192/)
[Iwata A, et al. Polo-like kinase 1 regulates tau phosphorylation and neurodegeneration. J Neurochem. 2010](https://pubmed.ncbi.nlm.nih.gov/20230264/)
[Liu Q, et al. PLK1-mediated phosphorylation of alpha-synuclein and dopaminergic neuronal death. Cell Death Differ. 2017](https://pubmed.ncbi.nlm.nih.gov/28537573/)
[Williams GL, et al. PLK1 inhibition as therapeutic strategy for Alzheimer's disease. J Alzheimers Dis. 2020](https://pubmed.ncbi.nlm.nih.gov/32116248/)See Also
- [PLK1 Gene](/genes/plk1)
- [Aurora Kinase B](/proteins/aurkb-protein)
- [Cell Cycle Kinases](/mechanisms/cell-cycle-arrest)
- [Tau Protein](/proteins/tau-protein)
- [Alpha-Synuclein](/proteins/alpha-synuclein)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
External Links
- [UniProt: O14988](https://www.uniprot.org/uniprot/O14988)
- [PDB structures](https://www.rcsb.org/search?q=uniprot:O14988)
- [GeneCards: PLK1](https://www.genecards.org/cgi-bin/carddisp.pl?gene=PLK1)
- [Allen Human Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=PLK1)
References
[Histidine N(τ)-cyclized macrocycles as a new genre of polo-like kinase 1 polo-box domain-binding inhibitors.](https://pubmed.ncbi.nlm.nih.gov/30174151/) (Bioorganic & medicinal chemistry letters, 2018, PMID:30174151)
[Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer.](https://pubmed.ncbi.nlm.nih.gov/29295989/) (Nature communications, 2018, PMID:29295989)
[Neighbor-directed histidine N (τ)-alkylation: A route to imidazolium-containing phosphopeptide macrocycles.](https://pubmed.ncbi.nlm.nih.gov/26152807/) (Biopolymers, 2015, PMID:26152807)