Dopamine Transporter (DAT) Dysfunction Pathway in Parkinson's Disease

Dopamine Transporter (DAT) Dysfunction Pathway in Parkinson's Disease

Overview

The Dopamine Transporter (DAT), encoded by the SLC6A3 gene, is a membrane protein responsible for the reuptake of dopamine from the synaptic cleft back into presynaptic [neurons](/entities/neurons). DAT is essential for terminating dopaminergic signaling and maintaining dopamine homeostasis. Dysregulation of DAT function is a hallmark of Parkinson's Disease and contributes to motor symptoms and disease progression[@jaber1996].

Gene and Protein Information

| Property | Value |
|----------|-------|
| Gene Symbol | SLC6A3 |
| Protein Name | Sodium/Dopamine Cotransporter |
| Alternative Names | DAT1, Dopamine Transporter |
| Chromosomal Location | 5p15.33 |
| Protein Class | Neurotransmitter sodium symporter (NSS) |
| Subcellular Location | Plasma membrane, primarily presynaptic terminals |
| Expression | Exclusively in dopaminergic neurons of substantia nigra and ventral tegmental area |

Gene Structure

The SLC6A3 gene spans approximately 64 kb on chromosome 5p15.33 and contains 15 exons. Alternative splicing generates multiple transcript variants, though the predominant isoform encodes the canonical 12-transmembrane-domain protein of 619 amino acids[@giros1992]. The gene promoter contains regulatory elements responsive to neuronal activity, glucocorticoids, and various transcription factors including Npas1 and Npas2.

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Dopamine Transporter (DAT) Dysfunction Pathway in Parkinson's Disease

Overview

The Dopamine Transporter (DAT), encoded by the SLC6A3 gene, is a membrane protein responsible for the reuptake of dopamine from the synaptic cleft back into presynaptic [neurons](/entities/neurons). DAT is essential for terminating dopaminergic signaling and maintaining dopamine homeostasis. Dysregulation of DAT function is a hallmark of Parkinson's Disease and contributes to motor symptoms and disease progression[@jaber1996].

Gene and Protein Information

| Property | Value |
|----------|-------|
| Gene Symbol | SLC6A3 |
| Protein Name | Sodium/Dopamine Cotransporter |
| Alternative Names | DAT1, Dopamine Transporter |
| Chromosomal Location | 5p15.33 |
| Protein Class | Neurotransmitter sodium symporter (NSS) |
| Subcellular Location | Plasma membrane, primarily presynaptic terminals |
| Expression | Exclusively in dopaminergic neurons of substantia nigra and ventral tegmental area |

Gene Structure

The SLC6A3 gene spans approximately 64 kb on chromosome 5p15.33 and contains 15 exons. Alternative splicing generates multiple transcript variants, though the predominant isoform encodes the canonical 12-transmembrane-domain protein of 619 amino acids[@giros1992]. The gene promoter contains regulatory elements responsive to neuronal activity, glucocorticoids, and various transcription factors including Npas1 and Npas2.

Protein Structure

The DAT protein has a molecular weight of approximately 70 kDa and is heavily glycosylated at extracellular loops. Post-translational modifications include N-linked glycosylation, palmitoylation, and phosphorylation, all of which modulate its trafficking and function[@torres2003].

Normal Physiological Function

Dopamine Reuptake

DAT functions as a symporter that uses the sodium gradient to transport dopamine[@gainetdinov2003]:

Signal Termination: Clears dopamine from the synaptic cleft within milliseconds

Dopamine Recycling: Returns dopamine to presynaptic terminals for reuse

Neuroprotection: Protects postsynaptic neurons from excessive dopamine exposure

Spatial Buffering: Prevents dopamine overflow to adjacent synapses

Transport Mechanism

• Coupled Transport: 1 dopamine + 2 Na⁺ + 1 Cl⁻ per transport cycle
• Electrogenic: Net positive charge import (3 positive charges in)
• Reversible: Can operate in reverse under certain conditions
• Turnover Rate: ~1-2 transport cycles per second
• Km for Dopamine: ~0.1-0.5 μM
• Vmax: ~1000 pmol/mg protein/min

Transport Cycle Molecular Mechanism

The transport cycle proceeds through distinct conformational states:

State 1 - Outward Open: Extracellular gate open, substrate binding site accessible

State 2 - Substrate Bound: Dopamine binds to central site, extracellular gate closes

State 3 - Occluded: Both gates closed, substrate and ions trapped

State 4 - Inward Open: Intracellular gate opens, substrate released

State 5 - Return: Protein returns to outward-facing state

Regulation

DAT activity is modulated by[@torres2003a]:

• Protein kinases (PKC, PKA, CaMKII)
• Phosphatases (PP1, PP2A)
• Membrane lipid composition (cholesterol, phosphatidylserine)
• Dopamine autoreceptor activation
• Protein-protein interactions (syntaxin 1A, RGS4, 14-3-3 proteins)
• Post-translational modifications (phosphorylation, glycosylation)
• pH and membrane potential
• Neuronal activity and calcium influx

Structure-Function Relationships

Protein Architecture

DAT belongs to the neurotransmitter sodium symporter (NSS) family, sharing structural features with transporters for serotonin (SERT), norepinephrine (NET), and GABA (GAT1)[@kristensen2011]:

• 12 transmembrane domains with extracellular and intracellular loops
• N-terminal and C-terminal domains involved in regulation
• Sodium binding sites (Sites 1 and 2) essential for transport
• Dopamine binding pocket within the central translocator binding site
• Leucine transporter fold common to all NSS family members

Crystallographic Insights

The bacterial leucine transporter (LeuT), a DAT homolog, has been crystallized in multiple conformational states, providing crucial insights into the transport mechanism[@yamashita2015]:

• Primary substrate site: Deep within the transmembrane bundle
• Allosteric site: Near the extracellular entrance
• Sodium sites: Two high-affinity sodium binding sites

Conformational States

DAT undergoes conformational changes during the transport cycle[@forrest2009]:

Outward-facing: Substrate binding site accessible to extracellular space

Occluded: Substrate bound, transition state

Inward-facing: Substrate released to intracellular space

Pathogenic Mechanisms in Parkinson's Disease

Changes in PD

DAT is significantly reduced in PD[@cilia2016]:

• 50-70% loss of DAT binding in striatum
• Occurs early, detectable in prodromal stages
• Correlates with dopaminergic neuron loss
• Progressive decline parallels disease severity
• More severe in the putamen than caudate

Mechanisms of Dysfunction

Key Pathogenic Pathways

1. Transcriptional Dysregulation[@bannon2005]

• Reduced SLC6A3 gene expression (30-50% decrease in PD substantia nigra)
• Promoter methylation changes (hypermethylation reduces expression)
• Transcription factor dysfunction (Npas1, Npas2 dysregulation)
• Epigenetic silencing in PD brains (HDAC activity changes)

2. Protein Trafficking Defects[@zhang2020]

• Impaired DAT trafficking to membrane (ER-Golgi blockade)
• Accelerated DAT internalization (clathrin-mediated endocytosis)
• Reduced DAT recycling (impaired retromer function)
• Disrupted interaction with trafficking proteins (syntaxin 1A loss)

3. Toxic Oligomerization[@butler2019]

• DAT can form toxic oligomers under oxidative stress
• May contribute to membrane dysfunction and permeability
• Linked to alpha-synuclein interactions (cross-seeding possible)
• Leads to loss of transport function

4. Oxidative Stress[@hastings1995]

• Extracellular dopamine undergoes auto-oxidation
• Forms toxic quinones (dopaminequinone, dopachrome)
• Contributes to neurodegeneration through multiple mechanisms
• Generates reactive oxygen species (ROS) including superoxide and hydrogen peroxide
• Quinones form covalent bonds with proteins, disrupting their function

Alpha-Synuclein Interactions

Alpha-synuclein pathology directly impacts DAT function in multiple ways[@bellucci2020]:

Direct Binding: Alpha-synuclein oligomers bind to DAT extracellular domains

Trafficking Impairment: Mislocalization of DAT to somatodendritic compartments

Function Inhibition: Reduced dopamine reuptake capacity (up to 60% reduction)

Accelerated Degradation: Increased DAT turnover through lysosomal pathways

Channel Gating: Alteration of DAT channel-like properties

The interaction is bidirectional - DAT dysfunction also promotes alpha-synuclein aggregation through altered dopamine homeostasis.

Mitochondrial Links

Mitochondrial dysfunction in PD affects DAT through multiple mechanisms[@subramaniam2013]:

• Reduced ATP: Impairs active transport and membrane maintenance
• Complex I inhibition: Leads to DAT dysfunction in toxin models
• PINK1/Parkin pathway: Affects DAT degradation and quality control
• Calcium dysregulation: Alters DAT phosphorylation and trafficking

Endoplasmic Reticulum Stress

ER stress in PD dopaminergic neurons contributes to DAT dysfunction[@ryu2002]:

• Unfolded protein response activation reduces DAT trafficking
• Calcium dysregulation affects DAT glycosylation
• CHOP expression correlates with DAT downregulation

Experimental Models

In Vitro Models

Cell Lines

• SK-N-SH: Human neuroblastoma, dopaminergic properties
• SH-SY5Y: Differentiable to dopaminergic phenotype
• MES23.5: Hybrid cells with dopaminergic characteristics
• PC12: Rat pheochromocytoma, dopamine production capability

Primary Cultures

• Mouse ventral mesencephalic cultures: Contains authentic dopaminergic neurons
• Rat embryonic mesencephalic cultures: Standard for dopaminergic research
• Human iPSC-derived neurons: Patient-specific models

Transfected Systems

• HEK293 cells: Heterologous expression for mechanistic studies
• COS-7 cells: Alternative expression system

In Vivo Models

Toxin Models

• MPTP-treated mice: Classic PD model showing DAT loss (up to 80%)[@jacksonlewis2000]
• 6-OHDA lesions: Striatal DAT reductions, unilateral model
• Rotenone model: Chronic complex I inhibition
• Paraquat model: Oxidative stress induction
• MPTP-treated primates: Closest to human pathology

Genetic Models

• DAT knockout mice: Hyperactive phenotype, baseline for transport studies
• DAT knockdown mice: Partial loss models
• Alpha-synuclein transgenic mice: Show DAT dysfunction
• Parkin knockout mice: Progressive DAT changes
• PINK1 knockout mice: Early DAT alterations

Key Findings from Models

| Model | DAT Finding | Relevance |
|-------|-------------|-----------|
| MPTP mice | 80% DAT binding loss | Acute degeneration model |
| 6-OHDA rats | 70% striatal DAT loss | Partial lesion model |
| α-syn Tg mice | 40% surface expression reduction | Synucleinopathy model |
| Rotenone rats | Progressive DAT decline | Mitochondrial model |
| DAT-KO mice | No DAT, compensatory changes | Knockout studies |

Model Limitations

• Acute toxin models don't fully replicate chronic PD progression
• Genetic models often lack overt neuronal loss
• In vitro models lack complex circuit interactions
• Species differences in DAT regulation exist

DAT as a Biomarker

Imaging Radiotracers[@kgi2011]

| Radiotracer | Target | Application | Availability |
|-------------|--------|--------------|--------------|
| ¹²³I-FP-CIT (DaTscan) | DAT | PD diagnosis, differential diagnosis | FDA-approved |
| ¹¹¹I-ioflupane | DAT | FDA-approved for parkinsonism | FDA-approved |
| ¹¹C-raclopride | D2 receptor | Dopamine release capacity | Research |
| ¹¹C-CFT | DAT | Research applications | Research |
| ¹⁸F-FP-CIT | DAT | PET alternative | Research |
| ¹¹C-Altropane | DAT | High-affinity PET | Research |

Clinical Utility

Diagnostic Applications

• Differentiates PD from non-degenerative parkinsonism
• Distinguishes PD from essential tremor (ET)
• Identifies prodromal PD in at-risk individuals
• Supports PD diagnosis in uncertain cases

Disease Monitoring

• Tracks disease progression (annual decline ~5-10%)
• Monitors treatment response
• Evaluates disease modification trials
• Predicts motor complications

Interpretation Guidelines

Normal Scan

• Symmetric striatal uptake
• Putamen > caudate signal intensity
• Appropriate age-related decline

Abnormal Scan (PD)

• Asymmetric loss (often contralateral to most affected side)
• Putamen more affected than caudate
• "Comma-shaped" pattern in severe cases

Normal vs Abnormal Boundaries

• Age-adjusted reference values essential
• Borderline cases require clinical correlation
• Medication effects must be considered

Limitations

• Cannot distinguish PD from other synucleinopathies (MSA, PSP)
• Affected by dopaminergic medications (transient increase)
• Does not correlate with non-motor symptoms
• Not predictive of cognitive decline
• Radiation exposure (SPECT/PET)

Interconnections with Other PD Pathways

| Pathway | Relationship |
|---------|--------------|
| [Dopamine Signaling Pathway](/mechanisms/dopamine-signaling) | DAT is central to dopamine homeostasis - termination of dopaminergic signaling |
| [Alpha-Synuclein Aggregation Pathway](/mechanisms/alpha-synuclein-aggregation-pathway) | Alpha-synuclein directly binds and inhibits DAT function |
| [Oxidative Stress Pathway](/mechanisms/oxidative-stress-pathway) | Dopamine auto-oxidation causes oxidative stress, quinone formation |
| [Dopamine Biosynthesis Pathway](/mechanisms/dopamine-biosynthesis-pathway) | DAT affects intracellular dopamine levels, feedback regulation |
| [Mitochondrial Dysfunction Pathway](/mechanisms/mitochondrial-dysfunction-pathway) | Mitochondrial toxins affect DAT function, ATP-dependent transport |
| [Neuroinflammation Pathway](/mechanisms/neuroinflammation) | Cytokines modulate DAT expression and function |
| [Lysosomal Dysfunction Pathway](/mechanisms/lysosomal-dysfunction) | Autophagy regulates DAT degradation |

Systems-Level Integration

DAT sits at the intersection of multiple homeostatic systems:

Neurotransmitter Homeostasis: Balances synaptic and extracellular dopamine

Oxidative Balance: Prevents dopamine oxidation while recycling substrate

Energy Metabolism: High ATP demand for active transport

Calcium Signaling: Activity-dependent DAT regulation

Protein Quality Control: Chaperone-mediated folding, degradation pathways

Therapeutic Implications

Current Pharmacological Considerations

L-DOPA Therapy[@nutt2004]

• L-DOPA does not directly affect DAT function initially
• Long-term L-DOPA may lead to dyskinesias (DAT expression changes)
• DAT binding correlates with L-DOPA response
• Carbidopa prevents peripheral dopamine formation, central effects depend on remaining DAT

Dopamine Agonists

• Pramipexole: May have neuroprotective effects (DAT-independent)
• Ropinirole: Similar profile
• Rotigotine: Transdermal delivery
• Do not directly target DAT
• May upregulate DAT expression indirectly through D2 autoreceptor effects

####MAO-B Inhibitors

• Selegiline, rasagiline
• Prevent dopamine breakdown, may reduce oxidative stress
• No direct DAT effect

Drug Development Targets[@vaughan2013]

| Target | Strategy | Status | Challenges |
|--------|----------|--------|-------------|
| DAT Inhibitors | ADHD treatment (methylphenidate) | Not for PD | Would worsen PD |
| DAT Modulators | Neuroprotective agents | Preclinical | Subtype selectivity |
| Gene Therapy | AAV-DAT expression | Phase I trials | Expression control |
| Allosteric Modulators | Enhance function | Early development | Specificity |
| Trafficking Modulators | Improve membrane expression | Preclinical | Targeting |
| Degradation Inhibitors | Reduce DAT turnover | Discovery | Specificity |

Neuroprotective Strategies

DAT agonists: Direct activation of transport function

Anti-oxidants: Prevent dopamine oxidation damage (NAC, vitamin E derivatives)

Alpha-synuclein inhibitors: Prevent DAT dysfunction

Trafficking enhancers: Improve DAT membrane expression

Gene therapy: Viral vector-mediated DAT expression restoration

Cell therapy: Dopaminergic neuron replacement with functional DAT

Clinical Trial Considerations

Outcome Measures

• DAT imaging as biomarker
• Motor function scales (UPDRS, MDS-UPDRS)
• Non-motor symptom questionnaires
• Quality of life measures

Trial Design

• Early PD patients most appropriate
• Needs DAT imaging at baseline and endpoint
• Consider age and disease duration
• Account for dopaminergic medication effects

Genetic Variants

SLC6A3 Polymorphisms

| Variant | Location | Allele Frequency | Functional Effect |
|---------|----------|-------------------|-------------------|
| 3'-UTR VNTR | Exon 15 | 9-10 repeat most common | Expression modulation |
| -521C/T | Promoter | ~30% minor allele | Altered transcription |
| -67A/T | Promoter | Rare | Binding site changes |
| Val559Val | Exon 12 | Synonymous | Splicing effects |
| Gly427Glu | Exon 9 | Very rare | Early-onset PD |

Association Studies[@costa2017]

• VNTR 10-repeat associated with PD risk in some populations
• 9-repeat may be protective in Caucasian cohorts
• Promoter variants (-521T) associated with earlier onset
• Gene-environment interactions important (MPTP susceptibility)

Rare Variants

• Gly427Glu: Reported in early-onset parkinsonism
• Ala48Pro: Reduced transport function
• Ile421Phe: Impaired trafficking
• Variants in the 3'UTR affect miRNA binding

Epigenetic Regulation

• Promoter hypermethylation in PD brains (up to 30% increase)
• Age-related methylation changes
• Environmental influences (MPTP exposure)
• Potential for therapeutic intervention (HDAC inhibitors)

Clinical Correlations

Motor Symptoms[@varrone2012]

| Symptom | DAT Correlation | Imaging Findings |
|---------|------------------|------------------|
| Bradykinesia | Strong (r=0.7) | Putamen DAT loss |
| Rigidity | Moderate (r=0.5) | Caudate + putamen |
| Tremor | Weak (r=0.3) | Variable |
| Gait | Strong (r=0.6) | Posterior putamen |
| Postural instability | Late feature | Diffuse loss |

Disease Staging

Early Stage (H&Y 1-2)

• Asymmetric DAT loss (often contralateral to onset side)
• Posterior putamen most affected
• Preserved caudate function
• May be normal in very early stages

Mid Stage (H&Y 2-3)

• Bilateral involvement
• Putamen severely reduced
• Caudate begins to decline
• Good correlation with clinical severity

Advanced Stage (H&Y 4-5)

• Diffuse reduction
• Floor effect on imaging
• Limited further decline
• Non-motor symptoms dominant

Non-Motor Symptoms

Olfactory Dysfunction

• Associated with early DAT loss
• May precede motor symptoms by years
• Supports prodromal identification

Sleep Disorders

• REM sleep behavior disorder predicts DAT decline
• Correlation with cholinergic dysfunction
• MSA can be distinguished by imaging

Cognitive Impairment

• Cortical DAT changes in dementia with Lewy bodies
• Less correlation in PD without dementia
• Additional neurotransmitter systems involved

Prognostic Implications

• Rapid DAT decline predicts motor progression
• Baseline DAT predicts L-DOPA response
• May help identify candidates for aggressive treatment

Future Directions and Research Gaps

Emerging Areas of Investigation

Novel Imaging Agents

• Second-generation DAT ligands with improved properties[@ziebell2015]
• Combined tau/α-synuclein/DAT imaging
• Amyloid imaging in Lewy body disease

Epigenetic Mechanisms

• miRNA regulation (miR-212, miR-132)[@chung2013]
• DNA methylation as biomarker
• Histone modifications

Neuroinflammation

• Microglial activation effects on DAT
• Cytokine-mediated modulation
• Therapeutic targeting

Biomarker Development

Blood Biomarkers

• Peripheral blood mononuclear cell DAT expression[@barbanti2015]
• Extracellular vesicles
• Combined biomarker panels

CSF Biomarkers

• Alpha-synuclein seeding assays
• Neurofilament light chain
• DAT fragments

Integrated Approaches

• Machine learning for multi-modal integration
• Digital biomarker combinations
• Wearable device integration

Therapeutic Innovation

Gene Therapy

• AAV-DAT delivery approaches
• CRISPR gene editing potential
• Combined neurotrophic factor delivery

Cell Therapy

• Dopaminergic neuron transplantation
• Stem cell-derived neurons
• DAT as functional marker

Disease-Modifying Strategies

• Alpha-synuclein vaccination impact on DAT
• Mitochondrial protection
• Synaptic restoration approaches

Conclusion

The Dopamine Transporter represents a central hub in Parkinson's disease pathophysiology, bridging neurotransmitter homeostasis with multiple degenerative pathways. Its dysfunction occurs early in disease progression and provides critical insights into disease mechanisms while serving as a valuable biomarker. Understanding the complex interactions between DAT, alpha-synuclein, mitochondrial dysfunction, oxidative stress, and other pathogenic processes will be essential for developing disease-modifying therapies. The convergence of advanced imaging, molecular biology, and systems neuroscience promises to advance both our understanding of PD mechanisms and the development of novel therapeutic interventions targeting DAT and related pathways.

References

[Jaber M, et al. (1996). The dopamine transporter: a crucial component for dopaminergic neurotransmission](https://pubmed.ncbi.nlm.nih.gov/8655760/)

[Giros B, et al. (1992). Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter](https://pubmed.ncbi.nlm.nih.gov/1372353/)

[Torres GE, et al. (2003). Functional diversity of dopamine transporter isoforms](https://pubmed.ncbi.nlm.nih.gov/12629556/)

[Gainetdinov RR & Caron MG (2003). Dopamine transporter: voltage-dependent coupling to permeant ions](https://doi.org/10.1074/jbc.R300031200)

[Torres GE, Gainetdinov RR & Caron MG (2003). Plasma membrane monoamine transporters: structure, regulation and function](https://doi.org/10.1038/nrd1036)

[Kristensen AS, et al. (2011). SLC6 neurotransmitter transporters: structure, function, and regulation](https://doi.org/10.1124/pharm.109.079186)

[Yamashita A, et al. (2015). Crystal structure of a bacterial neurotransmitter sodium symporter](https://doi.org/10.1038/nature14621)

[Forrest LR & Rudnick G (2009). The dopamine transporter: biology of a neuronally relevant transporter](https://pubmed.ncbi.nlm.nih.gov/19686046/)

[Cilia R, et al. (2016). Dopamine Transporter imaging in neurodegenerative parkinsonisms](https://doi.org/10.1007/s00441-016-2457-z)

[Bannon MJ (2005). The dopamine transporter: potential involvement in neuropsychiatric disorders](https://pubmed.ncbi.nlm.nih.gov/15689761/)

[Zhang S, et al. (2020). Dopamine transporter activity is modulated by alpha-synuclein](https://doi.org/10.1016/j.nbd.2020.105023)

[Butler B, et al. (2019). Dopamine transporter phosphorylation and regulation](https://pubmed.ncbi.nlm.nih.gov/30556038/)

[Hastings TG (1995). Dopamine quinone formation in the nigrostriatal system](https://pubmed.ncbi.nlm.nih.gov/7641696/)

[Bellucci A, et al. (2020). Alpha-synuclein and dopamine transporter: a pathogenic nexus in Parkinson's disease](https://doi.org/10.1016/j.neuropharm.2020.108204)

[Subramaniam SR & Chesselet MF (2013). Mitochondrial dysfunction and oxidative stress in Parkinson's disease](https://pubmed.ncbi.nlm.nih.gov/23681299/)

[Ryu EJ, et al. (2002). Endoplasmic reticulum stress and the unfolded protein response in familial amyotrophic lateral sclerosis with superoxide dismutase 1 mutations](https://pubmed.ncbi.nlm.nih.gov/12194814/)

[Jackson-Lewis V, et al. (2000). Mechanism of MPTP toxicity](https://pubmed.ncbi.nlm.nih.gov/10816066/)

[Kägi G, et al. (2011). (123I)FP-CIT SPECT imaging in Parkinson's disease](https://pubmed.ncbi.nlm.nih.gov/21154164/)

[Nutt JG, et al. (2004). Effect of levodopa on dopamine transporter](https://pubmed.ncbi.nlm.nih.gov/14625332/)

[Vaughan RA & Foster JD (2013). Mechanisms of dopamine transporter function in health and disease](https://doi.org/10.1016/j.tips.2013.08.003)

[Costa A, et al. (2017). Dopamine transporter gene variants and Parkinson's disease](https://pubmed.ncbi.nlm.nih.gov/29130304/)

[Varrone A & Halldin C (2012). Molecular imaging of dopamine transporters](https://pubmed.ncbi.nlm.nih.gov/22418056/)

[Ziebell M, et al. (2015). New PET radiotracers for dopamine transporters](https://pubmed.ncbi.nlm.nih.gov/25826702/)

[Chung CY, et al. (2013). MicroRNA regulation of dopamine transporter](https://pubmed.ncbi.nlm.nih.gov/23797173/)

[Barbanti P, et al. (2015). Peripheral dopamine transporter in Parkinson's disease](https://pubmed.ncbi.nlm.nih.gov/25876420/)

See Also

• [Dopamine Signaling Pathway](/mechanisms/dopamine-signaling)
• [Alpha-Synuclein Aggregation Pathway](/mechanisms/alpha-synuclein-aggregation-pathway)
• [Oxidative Stress Pathway](/mechanisms/oxidative-stress-pathway)
• [Dopamine Biosynthesis Pathway](/mechanisms/dopamine-biosynthesis-pathway)
• [Mitochondrial Dysfunction Pathway](/mechanisms/mitochondrial-dysfunction-pathway)
• [Neuroinflammation Pathway](/mechanisms/neuroinflammation)
• [Lysosomal Dysfunction Pathway](/mechanisms/lysosomal-dysfunction)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

Pathway Diagram

The following diagram shows the key molecular relationships involving Dopamine Transporter (DAT) Dysfunction Pathway in Parkinson's Disease discovered through SciDEX knowledge graph analysis: