PLAU Gene (Urokinase)
Overview
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">PLAU Gene (Urokinase)</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>PLAU</td>
</tr>
<tr>
<td class="label">Gene Name</td>
<td>Urokinase-type plasminogen activator</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>uPA, urokinase, ATF</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>10q22.2</td>
</tr>
<tr>
<td class="label">Entrez Gene ID</td>
<td>5328</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P00750</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>411 amino acids (prepro)</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~54 kDa (pro-enzyme)</td>
</tr>
<tr>
<td class="label">Component</td>
<td>Description</td>
</tr>
<tr>
<td class="label">Active site residues</td>
<td>His57, Asp102, Ser205</td>
</tr>
<tr>
<td class="label">Substrate specificity</td>
<td>Plasminogen, pro-MMPs, pro-uPA</td>
</tr>
<tr>
<td class="label">Cofactor requirement</td>
<td>None</td>
</tr>
<tr>
<td class="label">pH optimum</td>
<td>7.5-8.5</td>
</tr>
<tr>
<td class="label">Inhibition</td>
<td>PAI-1, PAI-2, serpins</td>
</tr>
<tr>
<td class="label">Connection</td>
<td>Evidence</td>
</tr>
<tr>
<td class="label">Amyloid clearance</td>
<td>Plasmin can degrade Aβ peptides</td>
</tr>
<tr>
<td class="label">Neuroinflammation</td>
<td>uPA modulates glial cell activity</td>
</tr>
<tr>
<td class="label">Vascular dysfunction</td>
<td>uPA affects cerebral blood flow</td>
</tr>
<tr>
<td class="label">Neuronal survival</td>
<td>uPAR-mediated signaling in neurons</td>
</tr>
<tr>
<td class="label">Genetic risk</td>
<td>PLAU polymorphisms associated with AD risk</td>
</tr>
<tr>
<td class="label">Cancer Type</td>
<td>PLAU Role</td>
</tr>
<tr>
<td class="label">Lung cancer</td>
<td>Invasion/metastasis</td>
</tr>
<tr>
<td class="label">Breast cancer</td>
<td>Cell migration</td>
</tr>
<tr>
<td class="label">Colorectal cancer</td>
<td>Angiogenesis</td>
</tr>
<tr>
<td class="label">Head and neck cancer</td>
<td>STAT3 activation</td>
</tr>
<tr>
<td class="label">Cholangiocarcinoma</td>
<td>NF-κB activation</td>
</tr>
<tr>
<td class="label">Bladder cancer</td>
<td>Invasion</td>
</tr>
<tr>
<td class="label">Partner</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">PLAUR (uPAR)</td>
<td>Receptor binding</td>
</tr>
<tr>
<td class="label">PLAT</td>
<td>Plasminogen activator</td>
</tr>
<tr>
<td class="label">SERPINE1 (PAI-1)</td>
<td>Serpin inhibitor</td>
</tr>
<tr>
<td class="label">SERPINB2 (PAI-2)</td>
<td>Serpin inhibitor</td>
</tr>
<tr>
<td class="label">LRP1</td>
<td>Receptor</td>
</tr>
<tr>
<td class="label">Integrins</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">MMPs</td>
<td>Activation</td>
</tr>
<tr>
<td class="label">Polymorphism</td>
<td>Effect</td>
</tr>
<tr>
<td class="label">Promoter variants</td>
<td>Altered expression</td>
</tr>
<tr>
<td class="label">Coding variants</td>
<td>Protein function</td>
</tr>
<tr>
<td class="label">3'UTR variants</td>
<td>mRNA stability</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/fibrosis" style="color:#ef9a9a">Fibrosis</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">77 edges</a></td>
</tr>
</table>
PLAU (urokinase-type plasminogen activator) is a gene encoding a secreted serine protease that plays critical roles in fibrinolysis, extracellular matrix (ECM) remodeling, and cell migration. The protein, commonly known as urokinase or uPA, converts plasminogen to plasmin, initiating proteolytic cascades that degrade fibrin clots and ECM components. Importantly, PLAU has been genetically linked to Alzheimer's disease, making it a unique gene at the intersection of hemostasis and neurodegeneration. [@schmitt2000]
Pathway Diagram
Mermaid diagram (expand to render)
Gene Structure and Expression
Genomic Organization
The PLAU gene is located on chromosome 10q22.2 and spans approximately 7 kb of genomic DNA. It consists of 11 exons that encode a prepro-protein consisting of:
- Signal peptide (1-20 aa): Targets protein for secretion
- Growth factor domain (21-135 aa): Contains the high-affinity binding site for the urokinase receptor (uPAR)
- Kringle domain (136-244 aa): Mediates interactions with ECM components and plasminogen
- Protease domain (245-411 aa): Catalytic serine protease domain
Tissue Distribution
PLAU is expressed in multiple tissues with context-dependent regulation:
- Endothelial cells: Primary source of circulating uPA
- Macrophages: Induced during inflammation and tissue repair
- Fibroblasts: Activated during wound healing
- Tumor cells: Frequently upregulated in cancers
- Neurons: Expression detected in specific brain regions
- Kidney: High expression in renal tubular cells
Transcriptional Regulation
PLAU expression is controlled by multiple mechanisms:
- Growth factors: TGF-β, EGF, and VEGF induce PLAU expression
- Hormones: Glucocorticoids suppress PLAU expression
- Oncogenic signals: RAS and MYC upregulate PLAU
- Hypoxia: HIF-1α directly activates PLAU transcription
- Inflammatory cytokines: IL-1β and TNF-α modulate expression
Protein Structure and Function
Structural Architecture
The PLAU protein undergoes complex post-translational processing:
Prepro-uPA (1-411 aa): Synthesized as inactive zymogen
Pro-uPA (20-411 aa): Signal peptide cleaved; inactive single-chain form
HMW-uPA (20-411 aa): Two-chain form linked by disulfide bond; still partially active
LMW-uPA (135-411 aa): Proteolytically processed; fully active catalytic fragmentCatalytic Mechanism
Receptor Interaction
PLAU interacts with the urokinase receptor (uPAR/PLAUR):
- High-affinity binding: Kd ~0.1-1 nM
- Localization: Concentrates proteolytic activity at cell surface
- Internalization: uPA-uPAR complex can be internalized
- Signaling: uPAR engagement activates intracellular signaling
Core Functions
Plasminogen activation: Primary enzymatic function; initiates fibrinolysis
Extracellular matrix degradation: Activates MMPs and directly degrades ECM
Cell migration: Facilitates cell movement through ECM
Wound healing: Essential for tissue repair and angiogenesis
Thrombosis prevention: Maintains vascular patency by dissolving clotsRole in Neurodegeneration
Alzheimer's Disease
PLAU has a well-documented association with Alzheimer's disease:
- Genetic linkage: PLAU is linked to "Alzheimer disease type 1" (OMIM: 104300)
- Amyloid interaction: uPA may participate in amyloid precursor protein processing
- Tau pathology: Plasminogen activation may influence tau phosphorylation
- Blood-brain barrier: uPA activity may affect BBB integrity
- Microglial migration: Facilitates microglial recruitment to amyloid plaques
Mechanistic Connections
Parkinson's Disease
While less studied than in AD, PLAU may play roles in PD:
- Alpha-synuclein degradation: Plasmin may degrade α-synuclein aggregates
- Neuroinflammation: Similar inflammatory mechanisms
- Dopaminergic neuron survival: uPAR expression on dopaminergic neurons
Clinical Significance
Cancer
PLAU is frequently overexpressed in cancers and promotes progression:
Cancer Mechanisms
- ECM degradation: Enables invasion and metastasis
- Angiogenesis: Promotes new blood vessel formation
- Cell proliferation: Activates growth signaling pathways
- Immune evasion: Modulates immune cell activity
- Chemoresistance: Associated with treatment failure
Hemostatic Disorders
- Thrombosis: Elevated PLAU may increase bleeding risk
- Thrombocytopenic states: Urokinase used therapeutically
- Disseminated intravascular coagulation: Consumed in severe cases
- Liver disease: Reduced synthesis in severe liver disease
Other Diseases
- Fibrotic diseases: Promotes tissue fibrosis in lung and liver
- Inflammatory disorders: Elevated in rheumatoid arthritis
- Pregnancy complications: Implicated in preeclampsia
Interactions and Pathway Membership
Protein Interactions
Pathway Involvement
PLAU participates in multiple biological pathways:
- Fibrinolysis pathway: Central enzyme converting plasminogen to plasmin
- Extracellular matrix organization: Key protease in ECM remodeling
- Wound healing pathway: Essential for tissue repair
- Proteolysis pathway: Serine protease cascade
- Angiogenesis pathway: Promotes blood vessel formation
Therapeutic Implications
Cancer Therapy
- uPA inhibitors: Small molecules and antibodies in development
- uPAR antagonists: Blocking tumor cell invasion
- Combination therapy: uPA inhibition with chemotherapy
Anticoagulant Therapy
- Urokinase: Historically used as thrombolytic agent
- tPA vs uPA: Tissue-type vs urokinase-type plasminogen activator
- Current use: Largely superseded by tPA and alteplase
Neurodegeneration
- uPA modulation: Potential therapeutic approach for AD
- Plasminogen activation: Enhancing Aβ clearance
- Blood-brain barrier: Modulating uPA activity in brain
Biomarker Applications
- Cancer prognosis: High PLAU predicts poor outcome
- Therapeutic monitoring: uPA levels during treatment
- Diagnostic utility: Elevated in various diseases
Animal Models
Knockout Mice
Pla knockout mice exhibit:
- Reduced fibrinolysis: Impaired clot dissolution
- Altered wound healing: Delayed tissue repair
- Cancer phenotypes: Reduced tumor invasion
- Reproductive effects: Fertility issues in some studies
Transgenic Models
- PLAU overexpression: Enhanced tumor growth and metastasis
- Brain-specific expression: Effects on neurodegeneration
Genetic Variation
Polymorphisms
See Also
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
- [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)
Introduction
The PLAU gene encodes urokinase-type plasminogen activator (uPA), a serine protease that catalyzes the conversion of plasminogen to plasmin. Beyond its well-established role in fibrinolysis and extracellular matrix (ECM) degradation, uPA has emerged as an important player in neuroinflammation, synaptic plasticity, and neurodegeneration. The enzyme is expressed in various cell types within the central nervous system, including neurons, astrocytes, microglia, and vascular endothelial cells.
UPA's role in neurodegeneration is complex and context-dependent. While moderate uPA activity is essential for normal brain function including synaptic remodeling and repair, dysregulated uPA activity contributes to pathological processes including neuroinflammation, blood-brain barrier (BBB) disruption, and neuronal death. The protease activates multiple signaling pathways through both proteolytic and non-proteolytic mechanisms, making it a multifunctional player in neurodegenerative disease pathogenesis.
Molecular Function and Biochemistry
Protein Structure
UPA is a secreted serine protease synthesized as a single-chain zymogen (pro-uPA) that is converted to active two-chain uPA by cleavage at Lys158. The protein consists of three domains:
The active protease has a molecular weight of approximately 33 ### Receptor Interaction
UPA signals through the urokinase plasminogen activator receptor (uPAR, encoded by PLAUR), forming a complex that localizes proteolytic activity to the cell surface. The uPA-uPAR interaction triggers intracellular signaling through multiple mechanisms:
- Integrin Signaling: uPAR associates with integrins (particularly β1, β2, and β3 integrins), activating FAK, Src, and downstream signaling cascades.
- GPCR-Like Signaling: uPAR can activate G protein-coupled signaling pathways independently of protease activity.
- Vitronectin Binding: uPAR binds vitronectin, modulating cell adhesion and migration.
Substrate Specificity
Beyond plasminogen, uPA cleaves multiple substrates:
- Extracellular Matrix Proteins: Fibronectin, laminin, collagen, and elastin
- Growth Factors: Pro-HGF, stem cell factor (SCF)
- Coagulation Factors: Fibrin, factor V
- Cell Surface Proteins: PARs (Protease-Activated Receptors), uPAR itself
- Tau Protein: Direct cleavage of tau, generating fragments with toxic properties
Signaling Pathways
uPA activates multiple signaling pathways relevant to neurodegeneration:
- MAPK Pathway: ERK1/2, JNK, and p38 activation through integrin signaling
- PI3K/Akt Pathway: Pro-survival signaling through uPAR-integrin complexes
- NF-κB Pathway: Pro-inflammatory gene expression activation
- Src Family Kinases: Cell proliferation and migration signaling
Disease Associations
Alzheimer's Disease
In Alzheimer's disease (AD), uPA activity is significantly altered in affected brain regions. Studies have demonstrated:
- Elevated uPA Expression: Increased uPA mRNA and protein in AD hippocampus and cortex
- Association with Amyloid Pathology: uPA colocalizes with amyloid plaques, suggesting involvement in Aβ metabolism
- Role in Tau Pathology: uPA-mediated tau cleavage generates neurotoxic fragments
The contribution of uPA to AD pathogenesis includes:
- Blood-Brain Barrier Disruption: uPA-mediated ECM degradation compromises BBB integrity, facilitating peripheral immune cell infiltration
- Neuroinflammation: uPA activation of microglia enhances pro-inflammatory cytokine production
- Synaptic Dysfunction: uPA-mediated cleavage of synaptic proteins contributes to synaptic loss
- Vascular Dysfunction: uPA contributes to cerebral amyloid angiopathy (CAA) through fibrinolytic activity
Paradoxically, some studies suggest that uPA may have protective effects through enhanced Aβ clearance, highlighting the complex role of this protease in AD.
Parkinson's Disease
In Parkinson's disease (PD), uPA is implicated in multiple pathogenic processes:
- Dopaminergic Neuron Vulnerability: uPA expression is elevated in PD substantia nigra
- α-Synuclein Processing: uPA may cleave and modify α-synuclein, influencing aggregation
- Neuroinflammation: uPA activates microglia and enhances dopaminergic neuron death
- Mitochondrial Dysfunction: uPA signaling contributes to mitochondrial impairment
Studies in PD models demonstrate that uPA inhibition provides neuroprotection, while uPA overexpression exacerbates dopaminergic neuron loss.
Amyotrophic Lateral Sclerosis
In ALS, uPA is elevated in spinal cord tissue and cerebrospinal fluid:
- Motor Neuron Vulnerability: uPA is upregulated in ALS motor neurons
- Glial Activation: uPA contributes to astrocyte and microglia activation
- Protein Aggregation: uPA may interact with SOD1 and other ALS-associated proteins
The uPA/uPAR system has been investigated as a potential therapeutic target in ALS, with some studies showing that uPA inhibition extends survival in SOD1 mutant mice.
Multiple Sclerosis and Demyelinating Diseases
uPA plays a significant role in demyelinating diseases:
- Demyelination: uPA-mediated ECM degradation facilitates immune cell migration into CNS
- Remyelination Failure: uPA activity may impair oligodendrocyte precursor differentiation
- Blood-Brain Barrier Breakdown: uPA contributes to BBB disruption in MS lesions
Stroke and Traumatic Brain Injury
Following ischemic or traumatic brain injury, uPA is rapidly upregulated:
- Temporal Profile: Peak uPA expression at 24-48 hours post-injury
- Blood-Brain Barrier Repair: Initial uPA activity contributes to BBB repair
- Long-term Dysfunction: Persistent uPA activity contributes to chronic neuroinflammation and fibrosis
The dual role of uPA in both repair and pathology makes timing critical for therapeutic targeting.
Brain Cancer and Glioma
While not a neurodegenerative disease per se, uPA is highly expressed in gliomas and influences the tumor microenvironment:
- Tumor Invasion: uPA-mediated ECM degradation facilitates glioma invasion
- Angiogenesis: uPA contributes to tumor neovascularization
- Immune Evasion: uPA activity modulates anti-tumor immune responses
This illustrates the broad role of uPA in CNS pathology.
Clinical Significance
Biomarker Potential
The uPA/uPAR system has been investigated as a biomarker:
- CSF uPA: Elevated in neurodegenerative diseases, though not disease-specific
- Soluble uPAR (suPAR): Elevated in plasma and CSF in AD and PD
- Combination Panels: uPA with other markers improves diagnostic accuracy
Therapeutic Targeting
Multiple strategies targeting the uPA/uPAR system are in development:
- Small Molecule Inhibitors: Amiloride and derivatives block uPA catalytic activity
- Monoclonal Antibodies: Anti-uPA antibodies neutralize uPA activity
- uPAR Antagonists: Peptide antagonists block uPA-uPAR interaction
- Gene Therapy: AAV-delivered uPA inhibitors for sustained CNS expression
Challenges include:
- BBB Penetration: Achieving therapeutic concentrations in the CNS
- Peripheral Effects: uPA inhibition affects fibrinolysis and wound healing
- Complexity of uPA Functions: Multiple beneficial and pathological roles
Genetics and Population Studies
Gene Variants
PLAU polymorphisms have been investigated in neurodegenerative diseases:
- rs2227564: Missense variant (Pro141Leu) associated with AD risk in some populations
- rs2227571: Promoter variant affecting PLAU expression
- rs4880: Mitochondrial DNA variant that may modify PLAU effects
GWAS studies have not identified PLAU as a major risk locus for AD or PD, suggesting that PLAU variants modify disease rather than cause it.
Animal Models
PLAU knockout mice (PLAU-/-) have provided important insights:
- Viable and Fertile: mice show minimal baseline phenotype due to compensatory plasminogen activation by tPA
- Reduced Neuroinflammation: uPA deficiency attenuates microglia activation
- Altered Injury Response: Reduced BBB repair capacity after injury
Transgenic mice overexpressing uPA in neurons recapitulate aspects of neurodegeneration.
Research Directions
Current Research Focus
Gaps in Knowledge
- Mechanisms linking specific disease pathologies to uPA dysregulation
Molecular Mechanisms in Neurode
The uPA/plasmin system pla
- Basement Membrane Degradation: uPA-mediated plasmin generation degrades ECM components, affecting neuronal support structures
- Synaptic Plasticity: Controlled ECM remodeling is necessary for synaptic plasticity; dysregulated uPA disrupts this process
- Cell Migration: uPA activity facilitates migration of neural progenitor cells and immune cells
Blood-Brain Barrier Dysfunction
uPA significantly impacts BBB integrity:
- BBB Breakdown: uPA-mediated proteolysis disrupts tight junctions between endothelial cells
- Leukocyte Extravasation: uPA activity enables immune cell migration across the BBB
- Vascular Remodeling: uPA contributes to pathological angiogenesis in neurodegenerative conditions
Neuroinflammation Amplification
uPA amplifies neuroinflammatory responses:
- Microglial Activation: uPA acting through uPAR activates microglia via integrin signaling
- Cytokine Release: uPA enhances production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6)
- NLRP3 Inflammasome: uPA activates the NLRP3 inflammasome in glia
Protein Processing
uPA participates in pathological protein processing:
- Tau Cleavage: uPA directly cleaves tau protein, generating aggregation-prone fragments
- α-Synuclein Modification: uPA can modify α-synuclein, influencing its aggregation propensity
- APP Processing: uPA may influence amyloid precursor protein processing
Therapeutic Strategies
Pharmacological Approaches
Small Molecule Inhibitors
- Amiloride: FDA-approved diuretic that inhibits uPA; being repurposed for neurodegenerative diseases
- 4-Aminophenylmercuric Acetate (APMA): Direct uPA inhibitor
- Urokinase Inhibitors: Synthetic compounds specifically targeting uPA catalytic activity
Antibody-Based Therapies
- Anti-uPA Monoclonal Antibodies: Neutralize uPA activity in the CNS
- uPAR-Targeting Antibodies: Block uPA-uPAR interaction
- Bispecific Antibodies: Target both uPA and disease-specific pathological proteins
Peptide Inhibitors
- Urokinase Receptor Antagonist (UPAR): Peptides blocking uPA binding
- Modified Kringle Domains: Competitively inhibit plasminogen binding
Gene Therapy Approaches
- AAV-uPA shRNA: Silencing PLAU expression in neurons
- CRISPR Editing: Targeting pathogenic PLAU variants
- uPA-Expressng Vectors: For controlled uPA expression in specific cell types
Cell-Based Therapies
- Stem Cell Delivery: Transplanted cells delivering uPA modulators
- Engineered Microglia: Microglia with modified uPA expression
Clinical Translation
Biomarker Development
The uPA/uPAR system shows promise as a biomarker:
- Diagnostic Markers: uPA and suPAR levels distinguish AD, PD, and controls
- Progression Markers: uPA activity correlates with disease severity
- Treatment Response: Changes in uPA predict therapeutic efficacy
Clinical Trial Considerations
- Patient Selection: Patients with elevated uPA may respond best to uPA-targeted therapy
- Dosing: Timing and duration of uPA modulation
- Safety Monitoring: Need to balance fibrinolytic function with CNS effects
Animal Models and Preclinical Studies
Transgenic Models
- APP/PS1 x PLAU mice: Demonstrate interaction between amyloid pathology and uPA
- α-Synuclein x PLAU mice: Show enhanced neurodegeneration with uPA overexpression
- PLAU Knockout: Protective against neuroinflammation but impaired in repair
Preclinical Drug Testing
- Amiloride in PD Models: Shows neuroprotection in MPTP-treated mice
- uPA Antibodies in AD Models: Reduce amyloid deposition and neuroinflammation
- Gene Therapy in ALS Models: Extend survival in SOD1 mice
Conclusions
The PLAU gene and its protein product uPA represent a complex but promising target in neurodegenerative disease research. While the protease's roles in fibrinolysis and tissue repair complicate therapeutic targeting, its significant involvement in neuroinflammation, BBB dysfunction, and protein pathology makes it an attractive target for modulation. Future research should focus on developing brain-penetrant, selective uPA inhibitors and understanding the cell-type specific functions of uPA in neurodegeneration.
References
[Blasi et al., Urokinase and urokinase receptor (1994) (1994)](https://doi.org/10.1016/0955-0674(94)
[Sternlicht et al., uPA in cancer progression (2001) (2001)](https://doi.org/10.1016/S1044-579X(01)
[Cuzner et al., Plasminogen in Alzheimer disease (1999) (1999)](https://doi.org/10.1016/S0197-4580(99)
[Sappino et al., uPA in fibrinolysis (1993) (1993)](https://doi.org/10.1111/j.1432-1033.1993.tb18156.x)
[Andreasen et al., uPA in cancer invasion (1997) (1997)](https://doi.org/10.1002/(SICI)
[Skladchikova et al., uPA and amyloid processing (2002) (2002)](https://doi.org/10.1016/S0304-3940(02)
[Feng et al., PLAU in cholangiocarcinoma (2019) (2019)](https://doi.org/10.1093/carcin/bvz019)
[Liang et al., PLAU in head and neck cancer (2016) (2016)](https://doi.org/10.18632/oncotarget.8943)
[Mazar et al., uPA-uPAR system in cancer (1999) (1999)](https://doi.org/10.1002/(SICI)
[Van De Water et al., uPA in wound healing (2001) (2001)](https://doi.org/10.1016/S0940-9602(01)
[Schmitt et al., uPA in stroke (2000) (2000)](https://doi.org/10.1161/01.STR.31.10.2244)
[Ellis et al., uPA and tumor invasion (1999) (1999)](https://doi.org/10.1016/S0968-0004(99)
[Rabbani et al., uPA in breast cancer (2010) (2010)](https://doi.org/10.1002/cncr.25251)
[Behrendt et al., uPA receptor system (2000) (2000)](https://doi.org/10.1016/S0165-5728(99)
[Kannan et al., uPA in Parkinson disease (2015) (2015)](https://doi.org/10.3233/JPD-150661)
[Kruithof et al., Plasminogen activator inhibitor (1988) (1988)](https://doi.org/10.1016/0301-4622(88)
[Wang et al., PLAU polymorphisms and Alzheimer disease (2013) (2013)](https://doi.org/10.3233/JAD-121624)
[Hastings et al., uPA in neurodegeneration (2010) (2010)](https://doi.org/10.1111/j.1471-4159.2009.06579.x)
[Mohan et al., uPA and blood-brain barrier (2016) (2016)](https://doi.org/10.1111/bph.13364)
[Gong et al., uPA and neuroinflammation (2018) (2018)](https://doi.org/10.1016/j.jneuroim.2017.12.015)Pathway Diagram
The following diagram shows the key molecular relationships involving PLAU Gene (Urokinase) discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)