TGF-β Signaling in Parkinson's Disease
Overview
Transforming Growth Factor Beta (TGF-β) is a multifunctional cytokine that plays critical roles in neuronal survival, neuroinflammation modulation, and glial cell function. The TGF-β signaling pathway has emerged as an important player in Parkinson's disease (PD), with both neuroprotective and disease-modulating properties[@khalil2022]. TGF-β belongs to a larger superfamily that includes activins, inhibins, BMPs, and growth differentiation factors (GDFs), all sharing a conserved cysteine knot structure. In the CNS, TGF-β signaling serves as a master regulator of cellular homeostasis, coordinating responses to injury, regulating neuroinflammation, and maintaining the balance between neuronal survival and death. Dysregulation of TGF-β signaling has been documented across multiple PD models and patient samples, making it a compelling therapeutic target for disease modification rather than mere symptom management.
TGF-β Family and Receptors
The TGF-β family in mammals includes three isoforms[@khalil2022][@todorovic2020]:
- TGF-β1: Predominant in most tissues, involved in inflammation and immune regulation. In the CNS, TGF-β1 is primarily produced by microglia and astrocytes. It serves as the primary regulator of the neuroinflammatory response, with both pro- and anti-inflammatory actions depending on context and cellular environment.
- TGF-β2: Important in neuronal development and function. TGF-β2 is critical during embryonic CNS development for neuronal migration and circuit formation. In adulthood, it regulates synaptic plasticity and is implicated in long-term potentiation (LTP) and memory consolidation.
- TGF-β3: Critical for neuronal survival and migration. TGF-β3 shows the strongest neuroprotective effects among the three isoforms in several PD models. It is particularly important for the survival of midbrain dopaminergic neurons and promotes axonal regeneration after injury.
Each isoform has distinct expression patterns and functions in the central nervous system, with TGF-β1 and TGF-β2 being the most studied in neurodegeneration contexts.
Receptor System
TGF-β signals through a complex receptor system composed of type I, type II, and type III receptors:
Mermaid diagram (expand to render)
Receptor types:
- Type I receptors (ALK1-7): Serine/threonine kinases that propagate signals. ALK5 (TGF-beta RI) is the primary type I receptor for TGF-beta in most cell types. ALK1 is predominantly expressed in endothelial cells and can signal through SMAD1/5/8 (BMP pathway) when activated by TGF-beta.
- Type II receptors (TGF-beta RII, BMPRII): Ligand-binding receptors that constitutively phosphorylate type I receptors upon ligand binding. TGF-beta RII is expressed on dopaminergic neurons, astrocytes, and microglia.
- Type III receptors (betaglycan, endoglin): Co-receptors that modulate ligand binding and presentation to type I/II complexes. Betaglycan can present TGF-beta2 to TGF-beta RII with higher affinity.
TGF-β Latency and Activation
TGF-β is secreted in a latent form bound to latent TGF-β binding proteins (LTBPs) and the latent TGF-β binding complex (LLC). Activation requires release from this latent complex through several mechanisms:
- Integrin-mediated activation: Especially αVβ6 and αVβ8 integrins on epithelial and endothelial cells
- Proteolytic cleavage: By matrix metalloproteinases (MMPs), plasmin, and thrombin
- pH and ROS: Acidic environments and reactive oxygen species can trigger conformational release
- Mechanical force: Stretch and shear stress in the extracellular matrix
Receptor Trafficking and Signaling Kinetics
TGF-β receptor complexes undergo clathrin-mediated endocytosis, which serves both to attenuate and potentiate signaling depending on the route:
Mermaid diagram (expand to render)
TGF-β in the Healthy Brain
Neuronal Expression
TGF-β receptors are widely expressed in the brain[@todorovic2020]:
- Dopaminergic neurons in the substantia nigra pars compacta (SNc)
- GABAergic neurons in the striatum and cortex
- Glutamatergic neurons in the hippocampus and cortex
- Astrocytes and microglia throughout the CNS
- Oligodendrocyte precursor cells (OPCs)
The expression pattern suggests TGF-β plays both developmental and maintenance roles across multiple neuronal populations.
Neurotrophic Functions
TGF-β signaling promotes[@todorovic2020][@chhor2023]:
Neuronal survival: Activation of PI3K/Akt and MAPK/ERK pro-survival cascades. TGF-β1 has been shown to reduce caspase-3 activation and prevent apoptotic cell death in models of oxidative stress.
Synaptic plasticity: Regulation of synaptic formation and function through SMAD-dependent regulation of synaptic protein expression (PSD-95, synapsin, VGLUTs).
Neurogenesis: Support of adult hippocampal neurogenesis through activation of neural stem cell populations in the subgranular zone of the dentate gyrus.
Axonal growth: Guidance and regeneration via regulation of cytoskeletal dynamics through Rho GTPase modulation.TGF-β signaling undergoes age-related decline in the CNS[@warburton2022]:
| Factor | Young Adult | Aged (>65) | Change |
|--------|-------------|------------|--------|
| TGF-β1 brain levels | Baseline | 30-40% decrease | Reduced |
| TGF-β RII expression | Baseline | 25% decrease | Reduced |
| SMAD3 phosphorylation | Robust | Diminished | Impaired |
| p300/CBP coactivator | Available | Sequestered | Reduced |
| Target gene transcription | 100% | 45-55% | Declined |
This age-related decline may contribute to the increased vulnerability of dopaminergic neurons in older individuals, explaining the late-onset nature of idiopathic PD.
TGF-β Signaling in PD
SMAD-Dependent Pathway
The canonical TGF-β pathway utilizes SMAD proteins[@khalil2022]:
Mermaid diagram (expand to render)
Non-Canonical Pathways
TGF-β also activates non-SMAD pathways[@suh2024]:
- MAPK/ERK: Mediates cell survival and proliferation. ERK activation by TGF-β RI can phosphorylate MSK1/2, which in turn phosphorylates CREB.
- PI3K/Akt: Primary pro-survival pathway. Akt phosphorylates and inhibits pro-apoptotic proteins including BAD and FOXO transcription factors.
- Rho GTPases: Regulate cytoskeletal dynamics, cell shape, and migration. TGF-β can activate both RhoA (leading to stress fiber formation) and Rac1 (leading to lamellipodia).
- TAK1/NLK: TGF-β activated kinase 1 (TAK1) is a MAPKKK that activates both JNK/p38 and NF-κB pathways[@suh2024]. TAK1 is emerging as a critical node in TGF-β-mediated neuroinflammation in PD.
Single-Cell Transcriptomics Insights
Recent single-cell RNA sequencing studies have revealed pathway alterations in PD substantia nigra[@valencia2023]:
- TGF-β/SMAD target genes are downregulated in dopaminergic neurons from PD patients vs. age-matched controls
- Microglial TGF-β signaling is altered, with increased expression of TGF-β1 but reduced SMAD7 (inhibitory SMAD) — suggesting a compensatory but incomplete response
- Astrocytes show reduced ALK5 expression, potentially limiting their responsiveness to TGF-β
- A specific subpopulation of dopaminergic neurons with high TGF-β pathway activity shows relative preservation in PD, suggesting TGF-β signaling may mark neurons resistant to degeneration
TGF-β Dysfunction in PD
Altered Expression
Studies in PD models and patients show[@bjurstedt2019][@kane2018][@tate2012]:
| Parameter | Finding | Reference |
|-----------|---------|-----------|
| TGF-β1 CSF | Decreased 40% in PD patients vs. controls | [@bjurstedt2019] |
| TGF-β1 SNc | Reduced protein and mRNA in PD brains | [@kane2018] |
| TGF-β RII | Altered expression pattern in PD SNc | [@kane2018] |
| SMAD3 phosphorylation | Impaired in MPTP and 6-OHDA models | [@tate2012] |
| p-SMAD3 nuclear localization | Reduced in PD patient neurons | [@chen2024] |
| TGF-β2 serum | Decreased in PD with rapid progression | [@kim2021] |
Mechanisms of Dysfunction
Oxidative stress: Impairs TGF-β receptor function through oxidation of cysteine residues in the kinase domain, reducing receptor autophosphorylation.
Alpha-synuclein: Interferes with SMAD signaling through direct protein-protein interaction, preventing SMAD complex formation and nuclear translocation[@bate2016].
Neuroinflammation: Altered TGF-β expression patterns driven by chronic microglial activation creates a feedback loop that paradoxically promotes further inflammation.
Mitochondrial dysfunction: Reduces TGF-β-mediated survival signaling by compromising ATP-dependent phosphorylation cascades.TGF-β and Mitophagy
A recently characterized axis links TGF-β/SMAD3 to mitophagy regulation[@chen2024]:
Mermaid diagram (expand to render)
In PINK1-deficient models, restoration of SMAD3 signaling partially rescues mitochondrial defects, suggesting therapeutic potential for the TGF-beta/PINK1 axis in genetic PD.
Neuroprotective Mechanisms
Anti-Apoptotic Effects
TGF-β protects dopaminergic neurons through multiple mechanisms[@zode2009][@chhor2023]:
Mermaid diagram (expand to render)
Modulation of Neuroinflammation
TGF-β has complex effects on neuroinflammation[@petersen2021][@suh2024]:
Microglial modulation:
- Promotes M2 (anti-inflammatory) phenotype through STAT6 and KLF4 activation
- Reduces pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6)
- Enhances phagocytic clearance of debris and protein aggregates
- TAK1 activation by TGF-β can both promote and suppress neuroinflammation depending on context and cell state[@suh2024]
Astrocyte regulation:
- Promotes astrocyte survival and reactivity toward a neuroprotective phenotype
- Modulates glutamate uptake via GLT-1 regulation, preventing excitotoxicity
- Supports blood-brain barrier integrity through tight junction protein expression
TGF-β and Extracellular Vesicles
TGF-β1 modulates alpha-synuclein secretion via extracellular vesicles (EVs)[@lee2023]:
- TGF-β1 treatment reduces EV-mediated alpha-synuclein release from neurons
- TGF-β1 alters the cargo profile of EVs, favoring neuroprotective payloads
- EVs from TGF-β1-treated cells can transfer neuroprotective effects to recipient neurons
- This suggests TGF-β1 may help reduce the propagation of alpha-synuclein pathology
Interaction with PD Proteins
Alpha-Synuclein
TGF-β signaling interacts with alpha-synuclein pathology[@bate2016][@lee2023]:
- TGF-β can reduce alpha-synuclein aggregation through autophagy upregulation
- SMAD signaling intersects with alpha-synuclein toxicity pathways at multiple points
- TGF-β neuroprotection is reduced in α-synuclein overexpression models — suggesting a dominant-negative effect of pathological α-syn
- In PD patient-derived neurons, TGF-β1 treatment reduces intracellular α-syn accumulation and lowers extracellular release
LRRK2
LRRK2 mutations affect TGF-β signaling[@duson2021]:
- G2019S LRRK2 (most common PD mutation) alters SMAD-dependent transcription
- LRRK2 kinase activity phosphorylates SMAD1 at an atypical site, interfering with BMP-SMAD signaling cross-talk
- TGF-β responses are modified in LRRK2 mutation carriers, with reduced nuclear SMAD3 accumulation
- LRRK2 G2019S astrocytes show abnormal TGF-β1 secretion patterns, potentially contributing to non-cell autonomous toxicity
GBA
GBA mutations (Gaucher disease) impact TGF-β[@kim2021]:
- Lysosomal dysfunction affects TGF-β processing and activation
- GBA1 knockdown in neurons reduces latent TGF-β binding protein (LTBP) expression
- TGF-β signaling is impaired in GBA-associated PD, with reduced SMAD3 phosphorylation
- Restoration of GBA activity in iPSC models partially rescues TGF-β signaling deficits
PINK1/PARKIN
TGF-β/SMAD3 axis regulates mitophagy in PINK1-deficient models[@chen2024]:
- SMAD3 directly regulates PINK1 transcription
- Loss of PINK1 impairs TGF-β-dependent survival signaling
- The intersection of TGF-β and PINK1/PARKIN pathways creates a vulnerability amplification loop
BMP-TGF-β Cross-Talk
Shared Superfamily Membership
TGF-β and BMPs belong to the same TGF-β superfamily and share downstream SMAD effectors. This cross-talk creates complex signaling dynamics in the CNS[@park2024]:
Mermaid diagram (expand to render)
In dopaminergic neurons, BMP9 (endoglin ligand) promotes neurogenesis and survival, while TGF-beta1 primarily drives anti-inflammatory and survival responses. Dysregulation of either branch affects the other through competitive use of SMAD4 and shared inhibitory mechanisms.
Sex Differences in TGF-β Signaling
PD shows a male predominance (approximately 3:2 male-to-female ratio). TGF-β signaling exhibits sex differences that may contribute to this disparity[@hernandez2022]:
| Parameter | Male PD | Female PD | Reference |
|-----------|---------|-----------|-----------|
| CSF TGF-β1 | Reduced 45% vs. controls | Reduced 25% vs. controls | [@hernandez2022] |
| TGF-β RII on monocytes | Higher baseline, more decline | Lower baseline, stable | [@hernandez2022] |
| SMAD3 activation in SNc | Markedly reduced | Moderately reduced | [@hernandez2022] |
| TGF-β response to injury | Exaggerated inflammatory | Balanced response | [@hernandez2022] |
Estrogen has been shown to potentiate TGF-β signaling through direct transcriptional effects on the TGF-β1 promoter and through ERα-mediated interaction with SMAD coactivators. This may partially explain why females show slower PD progression despite similar initial vulnerability.
Therapeutic Implications
TGF-β as a Therapeutic Target
Agonist Strategies
Recombinant TGF-β:
- TGF-β1 administration shows neuroprotection in multiple PD models[@zode2009][@sortwell2016]
- Challenges: BBB penetration, dose optimization, and potential profibrotic effects
- Cell-type specificity requirements — targeting only neurons or astrocytes may reduce risks
Small molecule activators[@chhor2023]:
- Targeting TGF-β receptor agonists (ALK5 selective)
- SMAD pathway activators that bypass receptor defects
- Biased agonists that favor SMAD over MAPK pathways
Delivery Challenges
Nanoparticle-based delivery of TGF-β1 across the BBB has shown promise in PD models[@nguyen2023]:
- lipid-polymer hybrid nanoparticles loaded with TGF-β1 showed 8-fold higher brain accumulation vs. free drug
- Intravenous administration in MPTP mice reduced dopaminergic neuron loss by 60%
- No significant systemic toxicity or fibrotic complications observed at therapeutic doses
- Particle surface functionalization with anti-CD44 antibodies improved targeting to injured brain regions
Biomarker Potential
TGF-β levels as PD biomarkers[@bjurstedt2019][@crews2020][@kim2021]:
- CSF TGF-β1: Potential diagnostic and progression marker (40% decrease vs. controls)
- Blood TGF-β: Correlates with disease stage and motor progression rate
- TGF-β response: Predictive of therapeutic response to neuroprotective agents
- TGF-β1/TGF-β2 ratio: May distinguish PD subtypes (tremor-dominant vs. PIGD)
Clinical Evidence
Preclinical Studies
TGF-β neuroprotection has been demonstrated in multiple PD models[@zode2009][@sortwell2016][@tate2013][@duson2021]:
| Model | TGF-β Treatment | Outcome | Reference |
|-------|-----------------|---------|-----------|
| 6-OHDA rat | TGF-β1 intraventricular | Reduced DA neuron loss 55% | [@zode2009] |
| MPTP mouse | TGF-β1 intraperitoneal | Protected SNc neurons | [@sortwell2016] |
| α-syn tg mouse | TGF-β1 AAV vector | Reduced aggregation and fibril formation | [@tate2013] |
| LRRK2 G2019S | TGF-β1 modulation | Improved motor function, reduced inflammation | [@duson2021] |
| GBA N370S iPSC | TGF-β1 treatment | Partial rescue of lysosomal defects | [@kim2021] |
| PINK1 knockout | SMAD3 activator | Restored mitophagy, improved survival | [@chen2024] |
Clinical Data
TGF-β levels in PD patients[@bjurstedt2019][@crews2020][@kim2021][@hernandez2022]:
| Study | Sample | Finding | Significance |
|-------|--------|---------|--------------|
| Bjurstedt 2019 | 100 PD, 50 controls | CSF TGF-β1 decreased 40% | Diagnostic potential |
| Crews 2020 | 50 PD serum | TGF-β1 correlates with progression rate | Progression marker |
| Kim 2021 | 200 PD CSF | TGF-β1/TGF-β2 ratio altered by subtype | Subtype identification |
| Hernandez 2022 | 300 PD (150M/150F) | Sex-specific TGF-β1 differences | Sex-specific approaches |
| Valencia 2023 | Single-nucleus SNc | TGF-β pathway genes downregulated in PD neurons | Mechanistic insight |
Therapeutic Development
Drug Development Pipeline
| Agent | Type | Stage | Target | Notes |
|-------|------|-------|--------|-------|
| SB-525334 | Small molecule | Preclinical | TGF-β RI (ALK5) | Selective kinase inhibitor |
| Fresolimumab | Monoclonal antibody | Research | TGF-β1 | Neutralizing antibody |
| Gene therapy vectors | AAV-TGF-β1 | Preclinical | CNS expression | Sustained release approach |
| SMAD3 activators | Small molecule | Discovery | SMAD3 | Pathway bypass strategy |
| TGF-β1 nanoparticles | Nanoparticle delivery | Preclinical | BBB crossing | Targeted delivery[@nguyen2023] |
Clinical Trial Considerations
Patient Selection[@hernandez2022]:
- Early-stage PD (Hoehn & Yahr 1-2) to maximize residual neurons
- Preserved TGF-β signaling (baseline CSF assessment)
- No significant neuroinflammation comorbidities
- Male vs. female consideration for stratified treatment
Endpoints:
- CSF TGF-β1 as pharmacodynamic marker
- Dopamine transporter imaging (DAT-SPECT, DaTscan)
- Clinical motor scores (MDS-UPDRS Part III)
- Non-motor symptoms (MDS-UPDRS Part I)
Combination Approaches
TGF-β therapy may synergize with:
Levodopa: TGF-β enhances dopaminergic neuron survival, potentially extending the "honeymoon period" before motor complications develop
Neurotrophic factors: BDNF, GDNF combination — TGF-β upregulates neurotrophic factor receptors
Anti-inflammatory agents: Targeting complementary neuroinflammatory pathways (NLRP3, cGAS-STING)
Antioxidants: Nrf2 activators for combined protection against oxidative stress
Gene therapies: AAV-based GDNF delivery combined with TGF-β enhancementResearch Directions
Gene Therapy Approaches
- Viral vector delivery of TGF-β (AAV1, AAV2, AAV5 serotypes)
- Cell-type specific expression using CamKII or DAT promoters for neuronal targeting
- Regulated expression systems (tetracycline-inducible) for controlled dosing
- Combined gene therapy targeting multiple neuroprotective pathways
Small Molecule Development
Current focus on[@chhor2023][@nguyen2023]:
- BBB-penetrant TGF-β activators with favorable pharmacokinetics
- Receptor-selective agonists that favor SMAD over MAPK pathways
- SMAD pathway modulators that bypass receptor defects
- Nanoparticle formulations for targeted CNS delivery
Biomarker Development
- TGF-β1 as diagnostic marker (CSF-based assay)
- TGF-β response assays using patient-derived neurons for personalized medicine
- Disease progression monitoring through serial CSF measurements
- Therapeutic response prediction for patient stratification
SMAD Pathway in Detail
SMAD Protein Family
| SMAD | Type | Function | PD Relevance |
|------|------|----------|--------------|
| SMAD1 | R-SMAD | BMP signal transduction | Cross-talk with TGF-β |
| SMAD2 | R-SMAD | TGF-β signal transduction | Phosphorylation impaired in PD |
| SMAD3 | R-SMAD | Transcriptional activation | Nuclear translocation reduced in PD |
| SMAD4 | Co-SMAD | Complex formation | Partner availability maintained |
| SMAD5 | R-SMAD | BMP signal transduction | Compensatory for TGF-β defects |
| SMAD6 | I-SMAD | Negative regulation | Upregulated in PD — acts as brake |
| SMAD7 | I-SMAD | Negative regulation | Upregulated in PD microglia |
| SMAD8/9 | R-SMAD | BMP/GDF signal transduction | Limited PD-specific data |
SMAD-Dependent Transcription
TGF-β-activated SMAD complexes regulate[@khalil2022][@chen2024]:
Pro-survival genes: Bcl-2, Bcl-xL, c-IAP1/2, Survivin
Anti-inflammatory mediators: IL-10, TGF-β itself (autofeedback loop), SOCS proteins
Extracellular matrix: Collagen I/III/IV, fibronectin, MMPs (timing-dependent)
Cell cycle regulators: p21, p15, p57 (context-dependent growth arrest or survival)
Mitophagy regulators: PINK1 (direct transcriptional regulation)[@chen2024]SMAD Dysfunction in PD
In Parkinson's disease, SMAD signaling is impaired through[@tate2012][@chen2024]:
- Oxidative modification: Cysteine oxidation of SMAD3 at the DNA-binding domain, impairing transcription factor activity
- Altered phosphorylation: Reduced SMAD3 phosphorylation at the C-terminal serines (Ser423/425) due to impaired ALK5 kinase activity
- Nuclear import: Impaired nuclear translocation due to altered importin-α/β binding
- Transcriptional cofactors: Reduced p300/CBP availability due to competition with NF-κB for coactivator access
- Inhibitory SMAD upregulation: SMAD6/7 are upregulated in PD, creating a negative feedback loop
TGF-β in Glial Cells
Astrocyte Regulation
TGF-β modulates astrocyte function in PD[@petersen2021]:
- Glial fibrillary acidic protein (GFAP): Regulated expression — TGF-β1 can both increase (reactive astrocytes) and decrease (neuroprotective phenotype) GFAP depending on context
- Glutamate uptake: Enhanced by TGF-β through upregulation of GLT-1 (EAAT2), protecting against excitotoxicity
- Astrocytic support: Promotes secretion of neuroprotective factors (GDNF, BDNF, thrombospondins)
- Blood-brain barrier: Maintains tight junction integrity through ZO-1 and occludin regulation
Microglial Polarization
TGF-β drives microglial phenotype toward neuroprotection[@petersen2021][@suh2024]:
Mermaid diagram (expand to render)
Oligodendrocyte Interactions
TGF-β signaling in oligodendrocytes and OPCs:
- Promotes OPC survival and differentiation
- Regulates myelin basic protein (MBP) expression
- May influence the demyelination observed in some PD cases
- Interaction with GPR37/PSAP axis on oligodendrocyte function
TGF-β in Dopaminergic Neuron Development
Neurodevelopmental Perspective
TGF-β plays critical roles in midbrain dopaminergic neuron development[@park2024]:
- TGF-β2 and TGF-β3 gradients guide neural crest migration and differentiation
- SMAD-dependent signals are required for proper TH (tyrosine hydroxylase) expression
- BMP-TGF-β cross-talk during development shapes the nigrostriatal pathway
- Disruption of developmental TGF-β signaling may predispose to later vulnerability
Reprogramming and Regeneration
TGF-β pathway modulation can influence:
- Direct reprogramming of astrocytes to dopaminergic-like neurons
- Survival of transplanted ESC/iPSC-derived dopamine neurons
- In vitro differentiation of dopamine neurons from stem cells
Conclusion
TGF-β signaling represents a critical neuroprotective pathway in Parkinson's disease. Its multifaceted effects on neuronal survival, neuroinflammation, and glial function make it an attractive therapeutic target. The pathway is impaired at multiple levels in PD — from reduced ligand and receptor expression to defective SMAD signaling and increased inhibitory SMAD expression. Restoring TGF-β signaling through agonists, pathway activators, or targeted delivery represents a promising disease-modifying approach. The intersection of TGF-β signaling with known PD genes (LRRK2, GBA, PINK1, SNCA) and its role in sex differences underscores its central position in PD pathophysiology.
Key remaining questions include: (1) optimal delivery method for TGF-β therapeutics across the BBB, (2) whether receptor agonism vs. SMAD pathway activation is more effective, (3) timing of intervention relative to disease stage, and (4) how to account for sex differences in TGF-β signaling when designing clinical trials.
See Also
- [TGF-β/BMP Signaling Companies for PD](/companies/pd-tgf-beta-bmp-signaling-companies): Companies developing TGF-β and BMP neuroprotective therapies
- [TGF-β Signaling Pathway](/mechanisms/tgf-beta-signaling-pathway)
- [SMAD Signaling Pathway](/mechanisms/smad-signaling-pathway)
- [Neurotrophic Signaling](/mechanisms/neurotrophic-signaling-pathway)
- [LRRK2 Pathway in Parkinson's Disease](/mechanisms/lrrk2-kinase-pathway-parkinsons)
- [GBA Pathway in Parkinson's Disease](/mechanisms/gba-pathway-parkinsons)
- [Neuroinflammation in Parkinson's Disease](/mechanisms/neuroinflammation-parkinsons)