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PLK1 Protein (Polo-Like Kinase 1)

Protein Information

<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)

Protein Information

<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 brain

PLK1 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 unclear

Novel 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

Research Tools and Resources

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/)

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)

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PLK1PROTEIN

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📊 Evidence Profile

Evidence Balance

+0%

Certainty

45%

Debates

0

Incoming

9

Outgoing

11

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

plk1-protein

PLK1 Protein (Polo-Like Kinase 1)

Protein Information

Overview

Normal Cellular Function

Role in Mitosis

PLK1 Protein (Polo-Like Kinase 1)

Protein Information

Overview

Normal Cellular Function

Role in Mitosis

Non-Mitotic Functions in Neurons

Role in Alzheimer's Disease

Cell Cycle Re-Entry

Tau Phosphorylation

Synaptic Dysfunction

Amyloid Processing

Role in Parkinson's Disease

α-Synuclein Phosphorylation

Mitochondrial Dysfunction

Neuroinflammation

Role in Other Neurodegenerative Diseases

Amyotrophic Lateral Sclerosis

Huntington's Disease

Multiple Sclerosis

Therapeutic Targeting

PLK1 Inhibitors

Challenges for Neurodegeneration

Novel Therapeutic Strategies

Research Tools and Resources

Model Systems

Biomarkers

Key Publications

See Also

External Links

References

💬 Discussion

📗 Cite This Artifact

plk1-protein

PLK1 Protein (Polo-Like Kinase 1)

Protein Information

Overview

Normal Cellular Function

Role in Mitosis

PLK1 Protein (Polo-Like Kinase 1)

Protein Information

Overview

Normal Cellular Function

Role in Mitosis

Non-Mitotic Functions in Neurons

Role in Alzheimer's Disease

Cell Cycle Re-Entry

Tau Phosphorylation

Synaptic Dysfunction

Amyloid Processing

Role in Parkinson's Disease

α-Synuclein Phosphorylation

Mitochondrial Dysfunction

Neuroinflammation

Role in Other Neurodegenerative Diseases

Amyotrophic Lateral Sclerosis

Huntington's Disease

Multiple Sclerosis

Therapeutic Targeting

PLK1 Inhibitors

Challenges for Neurodegeneration

Novel Therapeutic Strategies

Research Tools and Resources

Model Systems

Biomarkers

Related Pathways

Key Publications

See Also

External Links

References

💬 Discussion