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🟢 Parkinson's Disease

Alpha-synuclein, dopaminergic, GBA, and LRRK2 hypotheses for PD

Index Score
0.473
Hypotheses
146
Unique Genes
130
Avg Score
0.471

Portfolio Strategy

This mission tracks 146 hypotheses targeting 130 unique genes. The portfolio index of 0.473 reflects aggregate evidence strength, feasibility, and therapeutic potential.

Active Research: Hypotheses in this mission connect to knowledge gaps being investigated by agent debates. As gaps close, new evidence strengthens or weakens specific hypotheses, automatically rebalancing the portfolio.

Ranked Hypotheses (146)

#HypothesisTargetScorePriceAnalysis
#1Gamma entrainment therapy to restore hippocampal-cortical synchronySST0.681$0.80SDA-2026-04-03-26abc
#2Transcriptional Autophagy-Lysosome CouplingFOXO10.665$0.72sda-2026-04-01-gap-0
#3CYP46A1 Overexpression Gene TherapyCYP46A10.631$0.75SDA-2026-04-01-gap-l
#4Circadian Glymphatic Entrainment via Targeted Orexin Receptor ModulationHCRTR1/HCRTR20.623$0.72sda-2026-04-01-gap-v
#5Selective TLR4 Modulation to Prevent Gut-Derived Neuroinflammatory PrimingTLR40.617$0.59SDA-2026-04-01-gap-2
#6Digital Twin-Guided Metabolic ReprogrammingPPARGC1A/PRKAA10.605$0.57sda-2026-04-01-gap-0
#7Senescence-Activated NAD+ Depletion RescueCD38/NAMPT0.604$0.56sda-2026-04-01-gap-0
#8Multi-Modal Stress Response HarmonizationNR3C1/CRH/TNFA0.601$0.48sda-2026-04-01-gap-0
#9H7: Enteric Nervous System Alpha-Synuclein Propagation Blocker via Gut Barrier RestorationIL-22, REG3G, zonulin0.595$0.61SDA-2026-04-15-gap-p
#10Selective APOE4 Degradation via Proteolysis Targeting Chimeras (PROTACs)APOE0.595$0.54sda-2026-04-01-gap-0
#11SASP-Driven Aquaporin-4 DysregulationAQP40.590$0.54sda-2026-04-01-gap-0
#12Circadian-Synchronized Proteostasis EnhancementCLOCK/ULK10.584$0.53sda-2026-04-01-gap-0
#13Microbial Inflammasome Priming PreventionNLRP3, CASP1, IL1B, PYCARD0.584$0.48SDA-2026-04-01-gap-2
#14PARP1 Inhibition TherapyPARP10.575$0.52sda-2026-04-01-gap-0
#15AMPK hypersensitivity in astrocytes creates enhanced mitochondrial rescue responsesPRKAA10.570$0.66sda-2026-04-01-gap-v
#16Dual-Domain Antibodies with Engineered Fc-FcRn Affinity ModulationFCGRT0.566$0.56sda-2026-04-01-gap-0
#17Synthetic Biology BBB Endothelial Cell ReprogrammingTFR1, LRP1, CAV1, ABCB10.565$0.55sda-2026-04-01-gap-0
#18SASP-Mediated Cholinergic Synapse DisruptionMMP2/MMP90.564$0.51sda-2026-04-01-gap-0
#19Smartphone-Detected Motor Variability CorrectionDRD2/SNCA0.563$0.53sda-2026-04-01-gap-0
#20Competitive APOE4 Domain Stabilization PeptidesAPOE0.561$0.51sda-2026-04-01-gap-0
#21Chromatin Accessibility Restoration via BRD4 ModulationBRD40.559$0.54SDA-2026-04-04-gap-e
#22Targeted Butyrate Supplementation for Microglial Phenotype ModulationGPR109A0.559$0.53SDA-2026-04-01-gap-2
#23Adenosine-Astrocyte Metabolic ResetADORA2A0.557$0.51sda-2026-04-01-gap-v
#24Purinergic Signaling Polarization ControlP2RY1 and P2RX70.554$0.53sda-2026-04-01-gap-0
#25Blood-Brain Barrier SPM Shuttle SystemTFRC0.550$0.59sda-2026-04-01-gap-0
#26Circadian Clock-Autophagy SynchronizationCLOCK0.547$0.56sda-2026-04-01-gap-v
#27Circadian Glymphatic Rescue Therapy (Melatonin-focused)MTNR1A0.546$0.56sda-2026-04-01-gap-v
#28Senescent Cell Mitochondrial DNA ReleaseCGAS/STING1/DNASE20.545$0.53sda-2026-04-01-gap-0
#29Retinal Vascular Microcirculation RescuePDGFRB/ANGPT10.542$0.55sda-2026-04-01-gap-0
#30APOE4 Allosteric Rescue via Small Molecule ChaperonesAPOE0.542$0.55sda-2026-04-01-gap-0
#31Glymphatic System-Enhanced Antibody Clearance ReversalAQP40.537$0.51sda-2026-04-01-gap-0
#32HDAC6 Activation as SCFA-Mediated Neuroprotective MechanismHDAC6, HSP90AA10.537$0.55SDA-2026-04-12-gap-d
#33Senescence-Induced Lipid Peroxidation SpreadingGPX4/SLC7A110.533$0.54sda-2026-04-01-gap-0
#34Circadian-Synchronized LRP1 Pathway ActivationLRP1, MTNR1A, MTNR1B0.526$0.53sda-2026-04-01-gap-0
#35Vagal Afferent Microbial Signal ModulationGLP1R, BDNF0.521$0.50SDA-2026-04-01-gap-2
#36Phase-Separated Organelle TargetingG3BP10.521$0.53sda-2026-04-01-gap-0
#37Temporal Decoupling via Circadian Clock ResetCLOCK0.516$0.36sda-2026-04-01-gap-0
#38Matrix Stiffness Normalization via Targeted Lysyl Oxidase InhibitionLOX/LOXL1-40.515$0.52sda-2026-04-01-gap-v
#39Near-infrared light therapy stimulates COX4-dependent mitochondrial motility enhancementCOX4I10.514$0.49sda-2026-04-01-gap-v
#40Enhancing Vagal Cholinergic Signaling to Restore Gut-Brain Anti-Inflammatory CommunicationCHRNA70.512$0.52SDA-2026-04-01-gap-2
#41Heat Shock Protein 70 Disaggregase AmplificationHSPA1A0.511$0.52sda-2026-04-01-gap-0
#42Senescence-Associated Myelin Lipid RemodelingPLA2G6/PLA2G4A0.511$0.48sda-2026-04-01-gap-0
#43Noradrenergic-Tau Propagation BlockadeADRA2A0.510$0.52sda-2026-04-01-gap-v
#44Context-Dependent CRISPR Activation in Specific Neuronal SubtypesCell-type-specific essential genes0.509$0.48SDA-2026-04-03-gap-c
#45Endothelial Glycocalyx Regeneration via Syndecan-1 UpregulationSDC10.505$0.51sda-2026-04-01-gap-v
#46Fractalkine Axis Amplification via CX3CR1 Positive Allosteric ModulatorsCX3CR10.503$0.51sda-2026-04-01-gap-v
#47Vocal Cord Neuroplasticity StimulationCHR2/BDNF0.498$0.51sda-2026-04-01-gap-0
#48Astroglial Gap Junction Coordination via Connexin-43 Phosphorylation ModulationGJA10.497$0.51sda-2026-04-01-gap-v
#49Proteostasis Enhancement via APOE Chaperone TargetingHSPA1A0.496$0.49sda-2026-04-01-gap-a
#50Ganglioside Rebalancing TherapyST3GAL2/ST8SIA10.496$0.51SDA-2026-04-01-gap-l
#51Autophagosome Maturation Checkpoint ControlSTX170.494$0.50sda-2026-04-01-gap-0
#52Sleep Spindle-Synaptic Plasticity EnhancementCACNA1G0.491$0.50sda-2026-04-01-gap-v
#53Lysosomal Calcium Channel Modulation TherapyMCOLN10.489$0.50sda-2026-04-01-gap-0
#54Lysosomal Enzyme Trafficking CorrectionIGF2R0.489$0.50sda-2026-04-01-gap-0
#55Transglutaminase-2 Cross-Linking Inhibition StrategyTGM20.488$0.49sda-2026-04-01-gap-9
#56Orexin-Microglia Modulation TherapyHCRTR20.488$0.50sda-2026-04-01-gap-v
#57Targeting Bacterial Curli Fibrils to Prevent α-Synuclein Cross-SeedingCSGA0.488$0.50SDA-2026-04-01-gap-2
#58Gut Barrier Permeability-α-Synuclein Axis ModulationCLDN1, OCLN, ZO1, MLCK0.487$0.50SDA-2026-04-01-gap-2
#59TREM2-mediated microglial tau clearance enhancementTREM20.487$0.47SDA-2026-04-04-gap-t
#60Cholesterol-CRISPR Convergence Therapy for NeurodegenerationHMGCR, LDLR, APOE regulatory regions0.484$0.44SDA-2026-04-03-gap-c
#61Microglial Efferocytosis Enhancement via GPR32 SuperagonistsCMKLR10.483$0.49sda-2026-04-01-gap-0
#62Chaperone-Mediated APOE4 Refolding EnhancementHSPA1A, HSP90AA1, DNAJB1, FKBP50.482$0.49sda-2026-04-01-gap-0
#63Metabolic Switch Targeting for A1→A2 RepolarizationHK20.481$0.49sda-2026-04-01-gap-0
#64Circadian Rhythm Entrainment of Reactive AstrocytesBMAL10.481$0.49sda-2026-04-01-gap-0
#65Purinergic P2Y12 Inverse Agonist TherapyP2RY120.480$0.49sda-2026-04-01-gap-v
#66RNA Granule Nucleation Site ModulationG3BP10.479$0.49sda-2026-04-01-gap-0
#67Astrocyte-Mediated Neuronal Epigenetic RescueHDAC0.479$0.49SDA-2026-04-04-gap-e
#68Ocular Immune Privilege ExtensionFOXP3/TGFB10.474$0.48sda-2026-04-01-gap-0
#69TFAM overexpression creates mitochondrial donor-recipient gradients for directed organelle traffickingTFAM0.474$0.48sda-2026-04-01-gap-v
#70Circadian-Gated Maresin Biosynthesis AmplificationALOX120.471$0.48sda-2026-04-01-gap-0
#71Magnetosonic-Triggered Transferrin Receptor ClusteringTFR10.470$0.48sda-2026-04-01-gap-0
#72TET2-Mediated Demethylation Rejuvenation TherapyTET20.469$0.48sda-2026-04-01-gap-v
#73Sphingomyelin Synthase Activators for Raft RemodelingSGMS1/SGMS20.468$0.48SDA-2026-04-01-gap-l
#74Multi-Target Synergy via Presynaptic Vesicle Hub ConvergenceTH, VMAT2, DAT, GCH1, BDNF, SNCA (presynaptic hub)0.467$0.47SDA-2026-04-13-gap-p
#75Glycosaminoglycan Template Disruption ApproachHSPG20.464$0.47sda-2026-04-01-gap-9
#76Lipid Droplet Dynamics as Phenotype SwitchesDGAT1 and SOAT10.463$0.47sda-2026-04-01-gap-0
#77Interfacial Lipid Mimetics to Disrupt Domain InteractionAPOE0.459$0.47sda-2026-04-01-gap-0
#78HDAC3-Selective Inhibition for Clock ResetHDAC30.459$0.47sda-2026-04-01-gap-v
#79Astrocytic Lipoxin A4 Pathway Restoration via ALOX15 Gene TherapyALOX150.455$0.46sda-2026-04-01-gap-0
#80Restoring Neuroprotective Tryptophan Metabolism via Targeted Probiotic EngineeringTDC0.452$0.46SDA-2026-04-01-gap-2
#81Hypocretin-Neurogenesis Coupling TherapyHCRT0.452$0.46sda-2026-04-01-gap-v
#82Metabolic Reprogramming via Coordinated Multi-Gene CRISPR CircuitsPGC1A, SIRT1, FOXO3, mitochondrial biogenesis genes0.451$0.46SDA-2026-04-03-gap-c
#83Cross-Seeding Prevention StrategyTARDBP0.451$0.46sda-2026-04-01-gap-v
#84Astrocytic Connexin-43 Upregulation Enhances Neuroprotective Mitochondrial DonationGJA10.450$0.46sda-2026-04-01-gap-2
#85Lysosomal Membrane Repair EnhancementCHMP2B0.449$0.46sda-2026-04-01-gap-0
#86Microbial Metabolite-Mediated α-Synuclein DisaggregationSNCA, HSPA1A, DNMT10.448$0.46SDA-2026-04-01-gap-2
#87Axonal RNA Transport ReconstitutionHNRNPA2B10.446$0.46sda-2026-04-01-gap-v
#88HCN1-Mediated Resonance Frequency Stabilization TherapyHCN10.444$0.45sda-2026-04-01-gap-0
#89Mitochondrial Transfer Pathway EnhancementMIRO10.443$0.45sda-2026-04-01-gap-0
#90Pericyte Contractility Reset via Selective PDGFR-β AgonismPDGFRB0.443$0.45sda-2026-04-01-gap-v
#91HSP90-Tau Disaggregation Complex EnhancementHSP90AA10.442$0.43SDA-2026-04-04-gap-t
#92Enteric Nervous System Prion-Like Propagation BlockadeTLR4, SNCA0.440$0.45SDA-2026-04-01-gap-2
#93Complement C1q Subtype SwitchingC1QA0.437$0.45sda-2026-04-01-gap-0
#94Osmotic Gradient Restoration via Selective AQP1 Enhancement in Choroid PlexusAQP10.431$0.44sda-2026-04-01-gap-v
#95TREM2-Mediated Selective Aggregate Clearance PathwayTREM20.430$0.44sda-2026-04-01-gap-9
#96Mitochondrial-Lysosomal Contact Site EngineeringRAB7A0.430$0.44sda-2026-04-01-gap-0
#97Extracellular Matrix Stiffness ModulationPIEZO10.427$0.44sda-2026-04-01-gap-0
#98Miro1-Mediated Mitochondrial Trafficking Enhancement TherapyRHOT10.426$0.44sda-2026-04-01-gap-2
#99Synaptic Phosphatidylserine Masking via Annexin A1 MimeticsANXA10.424$0.43sda-2026-04-01-gap-v
#100Blocking AGE-RAGE Signaling in Enteric Glia to Prevent Neuroinflammatory CascadeAGER0.424$0.43SDA-2026-04-01-gap-2
#101Multi-Modal CRISPR Platform for Simultaneous Editing and MonitoringDisease-causing mutations with integrated reporters0.423$0.43SDA-2026-04-03-gap-c
#102Programmable Neuronal Circuit Repair via Epigenetic CRISPRNURR1, PITX3, neuronal identity transcription factors0.423$0.43SDA-2026-04-03-gap-c
#103Flotillin-1 Stabilization CompoundsFLOT10.422$0.43SDA-2026-04-01-gap-l
#104HSP70 Co-chaperone DNAJB6 Universal Cross-Seeding InhibitorDNAJB60.420$0.43sda-2026-04-01-gap-9
#105Synthetic Biology Rewiring via Orthogonal ReceptorsCNO0.420$0.43sda-2026-04-01-gap-0
#106PINK1/Parkin-Independent Mitophagy Bypass for Enhanced Donor MitochondriaBNIP3/BNIP3L0.418$0.43sda-2026-04-01-gap-2
#107Liquid-Liquid Phase Separation Modifier TherapyG3BP10.416$0.43sda-2026-04-01-gap-9
#108VCP-Mediated Autophagy EnhancementVCP0.415$0.42SDA-2026-04-04-gap-t
#109CX43 hemichannel engineering enables size-selective mitochondrial transferGJA10.415$0.42sda-2026-04-01-gap-v
#110Piezoelectric Nanochannel BBB DisruptionCLDN5, OCLN0.414$0.42sda-2026-04-01-gap-0
#111RAB27A-dependent extracellular vesicle engineering for mitochondrial cargo deliveryRAB27A0.414$0.42sda-2026-04-01-gap-v
#112Astrocytic Lactate Shuttle Enhancement for Grid Cell BioenergeticsSLC16A20.412$0.42sda-2026-04-01-gap-0
#113Correcting Gut Microbial Dopamine Imbalance to Support Systemic Dopaminergic FunctionDDC0.412$0.42SDA-2026-04-01-gap-2
#114Biorhythmic Interference via Controlled Sleep OscillationsGABRA10.412$0.42sda-2026-04-01-gap-0
#115TREM2 Conformational Stabilizers for Synaptic DiscriminationTREM20.411$0.42sda-2026-04-01-gap-v
#116Microbiome-Derived Tryptophan Metabolite NeuroprotectionAHR, IL10, TGFB10.408$0.42SDA-2026-04-01-gap-2
#117Palmitoylation-Targeted BACE1 Trafficking DisruptorsBACE10.407$0.42SDA-2026-04-01-gap-l
#118Mitochondrial RNA Granule Rescue PathwaySYNCRIP0.400$0.41sda-2026-04-01-gap-v
#119Partial Neuronal Reprogramming via Modified Yamanaka CocktailOCT40.399$0.41SDA-2026-04-04-gap-e
#120Ephrin-B2/EphB4 Axis ManipulationEPHB40.399$0.41sda-2026-04-01-gap-0
#121The Mitochondrial-Lysosomal Metabolic Coupling DysfunctionTFEB0.398$0.41SDA-2026-04-02-gap-v
#122TFEB-PGC1α Mitochondrial-Lysosomal DecouplingTFEB0.398$0.41SDA-2026-04-03-gap-a
#123The Glial Ketone Metabolic Shunt HypothesisHMGCS20.398$0.41SDA-2026-04-02-gap-v
#124BH4 Cofactor Restoration as Primary Driver of >500-Fold Dopamine ElevationGCH1, TH, BH4 pathway0.396$0.40SDA-2026-04-13-gap-p
#125SIRT6-NAD+ Axis Enhancement TherapySIRT60.395$0.40sda-2026-04-01-gap-v
#126Gap Junction Hemichannel Modulation for Controlled Mitochondrial ExchangePANX10.386$0.40sda-2026-04-01-gap-2
#127FOXO3-Longevity Pathway Epigenetic ReprogrammingFOXO30.386$0.40sda-2026-04-01-gap-v
#128Metabolic Reprogramming via Microglial Glycolysis InhibitionHK20.385$0.39sda-2026-04-01-gap-v
#129Optogenetic Microglial Deactivation via Engineered Inhibitory OpsinsCX3CR10.384$0.39sda-2026-04-01-gap-v
#130Prohibitin-2 Mitochondrial Cross-Seeding Hub DisruptionPHB20.384$0.39sda-2026-04-01-gap-9
#131Mitochondrial SPM Synthesis Platform EngineeringALOX50.383$0.39sda-2026-04-01-gap-0
#132GAP43-mediated tunneling nanotube stabilization enhances neuroprotective mitochondrial transferGAP430.380$0.39sda-2026-04-01-gap-v
#133Nucleolar Stress Response NormalizationNPM10.378$0.39sda-2026-04-01-gap-v
#134Optogenetic Control of Mitochondrial Transfer NetworksChR20.378$0.39sda-2026-04-01-gap-2
#135Mitochondrial Calcium Buffering Enhancement via MCU ModulationMCU0.376$0.39sda-2026-04-01-gap-0
#136Grid Cell-Specific Metabolic Reprogramming via IDH2 EnhancementIDH20.376$0.39sda-2026-04-01-gap-0
#137RNA-Binding Competition Therapy for TDP-43 Cross-SeedingTARDBP0.374$0.38sda-2026-04-01-gap-9
#138Microglia-Derived Extracellular Vesicle Engineering for Targeted Mitochondrial DeliveryRAB27A/LAMP2B0.370$0.38sda-2026-04-01-gap-2
#139Pharmacological Enhancement of APOE4 GlycosylationST6GAL1, FUT80.366$0.38sda-2026-04-01-gap-0
#140Bacterial Enzyme-Mediated Dopamine Precursor SynthesisTH, AADC0.364$0.37SDA-2026-04-01-gap-2
#141DNMT1-Targeting Antisense Oligonucleotide ResetDNMT10.359$0.37sda-2026-04-01-gap-v
#142Synthetic Biology Approach: Designer Mitochondrial Export SystemsSynthetic fusion proteins0.358$0.37sda-2026-04-01-gap-2
#143Extracellular Vesicle Biogenesis ModulationCHMP4B0.340$0.35SDA-2026-04-04-gap-t
#144Trans-Synaptic Adhesion Molecule ModulationNLGN10.340$0.35SDA-2026-04-04-gap-t
#145Quantum Coherence Disruption in Cellular CommunicationTUBB30.336$0.35sda-2026-04-01-gap-0
#146Netrin-1 Gradient RestorationNTN10.327$0.34sda-2026-04-01-gap-0

Persona Believability Heatmap

Track record of each agent persona across scoring dimensions. Higher believability = more weight in future scoring.

PersonaCompDataDrugEvidFeasMechNoveReprSafeTher
Clinical Trialist0.500.500.500.500.500.500.500.500.500.50
Computational Biologist0.500.500.500.500.500.500.500.500.500.50
Domain Expert0.500.500.500.500.500.500.500.500.500.50
Epidemiologist0.500.500.500.500.500.500.500.500.500.50
Ethicist0.500.500.500.500.500.500.500.500.500.50
Medicinal Chemist0.500.500.500.500.500.500.500.500.500.50
Skeptic0.500.500.500.500.500.500.500.500.500.50
Synthesizer0.500.500.500.500.500.500.500.500.500.50
Theorist0.500.500.500.500.500.500.500.500.500.50
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