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🔮 Lysosomal / Autophagy

GBA, LRRK2 lysosomal, TFEB, and autophagy pathway hypotheses

Index Score
0.482
Hypotheses
91
Unique Genes
81
Avg Score
0.484

Portfolio Strategy

This mission tracks 91 hypotheses targeting 81 unique genes. The portfolio index of 0.482 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 (91)

#HypothesisTargetScorePriceAnalysis
#1Gamma entrainment therapy to restore hippocampal-cortical synchronySST0.681$0.80SDA-2026-04-03-26abc
#2Hippocampal CA3-CA1 circuit rescue via neurogenesis and synaptic preservationBDNF0.677$0.51SDA-2026-04-03-26abc
#3Nutrient-Sensing Epigenetic Circuit ReactivationSIRT10.670$0.77SDA-2026-04-04-gap-e
#4Transcriptional Autophagy-Lysosome CouplingFOXO10.665$0.72sda-2026-04-01-gap-0
#5Selective Acid Sphingomyelinase Modulation TherapySMPD10.648$0.76SDA-2026-04-01-gap-l
#6CYP46A1 Overexpression Gene TherapyCYP46A10.631$0.75SDA-2026-04-01-gap-l
#7APOE-Dependent Autophagy RestorationMTOR0.615$0.66sda-2026-04-01-gap-a
#8Selective APOE4 Degradation via Proteolysis Targeting Chimeras (PROTACs)APOE0.595$0.54sda-2026-04-01-gap-0
#9Circadian-Synchronized Proteostasis EnhancementCLOCK/ULK10.584$0.53sda-2026-04-01-gap-0
#10Microbial Inflammasome Priming PreventionNLRP3, CASP1, IL1B, PYCARD0.584$0.48SDA-2026-04-01-gap-2
#11PARP1 Inhibition TherapyPARP10.575$0.52sda-2026-04-01-gap-0
#12TFEB Nuclear Translocation to Reset Lysosomal-Hypoxia AxisTFEB, MTOR0.575$0.57SDA-2026-04-13-gap-p
#13AMPK hypersensitivity in astrocytes creates enhanced mitochondrial rescue responsesPRKAA10.570$0.66sda-2026-04-01-gap-v
#14ER Stress Reduction as Adjunctive Therapy to Support AutophagyHFE (H63D variant)0.566$0.57SDA-2026-04-15-gap-p
#15Dual-Domain Antibodies with Engineered Fc-FcRn Affinity ModulationFCGRT0.566$0.56sda-2026-04-01-gap-0
#16Synthetic Biology BBB Endothelial Cell ReprogrammingTFR1, LRP1, CAV1, ABCB10.565$0.55sda-2026-04-01-gap-0
#17Chromatin Accessibility Restoration via BRD4 ModulationBRD40.559$0.54SDA-2026-04-04-gap-e
#18PIKFYVE Inhibition Activates Aggregate Exocytosis via PI(3,5)P2→TRPML1→Calcineurin→TFEB Cascade in ALS Motor NeuronsPIKFYVE/MCOLN1/PPP3CB/TFEB0.559$0.56SDA-2026-04-13-gap-p
#19Circadian Clock-Autophagy SynchronizationCLOCK0.547$0.56sda-2026-04-01-gap-v
#20Circadian Glymphatic Rescue Therapy (Melatonin-focused)MTNR1A0.546$0.56sda-2026-04-01-gap-v
#21Senescent Cell Mitochondrial DNA ReleaseCGAS/STING1/DNASE20.545$0.53sda-2026-04-01-gap-0
#22APOE4 Allosteric Rescue via Small Molecule ChaperonesAPOE0.542$0.55sda-2026-04-01-gap-0
#23HDAC6 Activation as SCFA-Mediated Neuroprotective MechanismHDAC6, HSP90AA10.537$0.55SDA-2026-04-12-gap-d
#24C9orf72-SMCR8-WDR41 Complex Dysfunction in C9-ALS Rescued by PIKFYVE Inhibition via Lysosomal Exocytosis RestorationC9orf72/SMCR8/RAB7A/PIKFYVE0.537$0.54SDA-2026-04-13-gap-p
#25Targeted APOE4-to-APOE3 Base Editing TherapyAPOE0.526$0.53sda-2026-04-01-gap-0
#26Phase-Separated Organelle TargetingG3BP10.521$0.53sda-2026-04-01-gap-0
#27TBK1 Loss-of-Function Amplifies C1q-Mediated Synapse Elimination Through Type I IFN HyperactivationTBK10.520$0.52SDA-2026-04-13-gap-p
#28Cell-Type Specific TREM2 Upregulation in DAM MicrogliaTREM20.519$0.49analysis-SEAAD-20260
#29GFAP-Positive Reactive Astrocyte Subtype DelineationGFAP0.518$0.48analysis-SEAAD-20260
#30Heat Shock Protein 70 Disaggregase AmplificationHSPA1A0.511$0.52sda-2026-04-01-gap-0
#31Senescence-Associated Myelin Lipid RemodelingPLA2G6/PLA2G4A0.511$0.48sda-2026-04-01-gap-0
#32SIRT3-Mediated Mitochondrial Deacetylation Failure with PINK1/Parkin Mitophagy DysfunctionSIRT30.509$0.36SDA-2026-04-03-gap-s
#33TREM2-SYK Signaling Axis Couples OxPC Recognition to Phagocytic ClearanceTREM2 (Triggering receptor expressed on myeloid cells 2) + SYK (spleen tyrosine kinase)0.505$0.51SDA-2026-04-13-gap-p
#34Vocal Cord Neuroplasticity StimulationCHR2/BDNF0.498$0.51sda-2026-04-01-gap-0
#35Ganglioside Rebalancing TherapyST3GAL2/ST8SIA10.496$0.51SDA-2026-04-01-gap-l
#36Autophagosome Maturation Checkpoint ControlSTX170.494$0.50sda-2026-04-01-gap-0
#37Stress Granule Phase Separation ModulatorsG3BP10.490$0.50sda-2026-04-01-gap-v
#38Lysosomal Calcium Channel Modulation TherapyMCOLN10.489$0.50sda-2026-04-01-gap-0
#39Lysosomal Enzyme Trafficking CorrectionIGF2R0.489$0.50sda-2026-04-01-gap-0
#40Transglutaminase-2 Cross-Linking Inhibition StrategyTGM20.488$0.49sda-2026-04-01-gap-9
#41Orexin-Microglia Modulation TherapyHCRTR20.488$0.50sda-2026-04-01-gap-v
#42TREM2-mediated microglial tau clearance enhancementTREM20.487$0.47SDA-2026-04-04-gap-t
#43Metabolic Switch Targeting for A1→A2 RepolarizationHK20.481$0.49sda-2026-04-01-gap-0
#44RNA Granule Nucleation Site ModulationG3BP10.479$0.49sda-2026-04-01-gap-0
#45Trinucleotide Repeat Sequestration via CRISPR-Guided RNA TargetingHTT, DMPK, repeat-containing transcripts0.479$0.44SDA-2026-04-03-gap-c
#46Astrocyte-Mediated Neuronal Epigenetic RescueHDAC0.479$0.49SDA-2026-04-04-gap-e
#47Metabolic Circuit Breaker via Lipid Droplet ModulationPLIN20.476$0.48sda-2026-04-01-gap-0
#48Circadian-Gated Maresin Biosynthesis AmplificationALOX120.471$0.48sda-2026-04-01-gap-0
#49Sphingomyelin Synthase Activators for Raft RemodelingSGMS1/SGMS20.468$0.48SDA-2026-04-01-gap-l
#50Arginine Methylation Enhancement TherapyPRMT10.463$0.47sda-2026-04-01-gap-0
#51Lipid Droplet Dynamics as Phenotype SwitchesDGAT1 and SOAT10.463$0.47sda-2026-04-01-gap-0
#52HDAC3-Selective Inhibition for Clock ResetHDAC30.459$0.47sda-2026-04-01-gap-v
#53Astrocytic Lipoxin A4 Pathway Restoration via ALOX15 Gene TherapyALOX150.455$0.46sda-2026-04-01-gap-0
#54Metabolic Reprogramming via Coordinated Multi-Gene CRISPR CircuitsPGC1A, SIRT1, FOXO3, mitochondrial biogenesis genes0.451$0.46SDA-2026-04-03-gap-c
#55Lysosomal Membrane Repair EnhancementCHMP2B0.449$0.46sda-2026-04-01-gap-0
#56Microbial Metabolite-Mediated α-Synuclein DisaggregationSNCA, HSPA1A, DNMT10.448$0.46SDA-2026-04-01-gap-2
#57Oligodendrocyte Protectin D1 Mimetic for Myelin ResolutionGPR370.447$0.46sda-2026-04-01-gap-0
#58MITF Acts as the Primary Transcriptional Effector Downstream of HDAC1/2 Deletion, Driving the DAM2 Lysosomal Program Through De-repression of Phagocytic EnhancersMITF0.444$0.44SDA-2026-04-13-gap-p
#59Sphingolipid Metabolism ReprogrammingCERS20.443$0.45sda-2026-04-01-gap-0
#60HSP90-Tau Disaggregation Complex EnhancementHSP90AA10.442$0.43SDA-2026-04-04-gap-t
#61Enteric Nervous System Prion-Like Propagation BlockadeTLR4, SNCA0.440$0.45SDA-2026-04-01-gap-2
#62APOE Isoform Conversion TherapyAPOE0.437$0.45sda-2026-04-01-gap-a
#63LRP1-Dependent Tau Uptake DisruptionLRP10.437$0.45SDA-2026-04-04-gap-t
#64Aquaporin-4 Polarization Enhancement via TREK-1 Channel ModulationKCNK20.437$0.45sda-2026-04-01-gap-v
#65TREM2-Mediated Selective Aggregate Clearance PathwayTREM20.430$0.44sda-2026-04-01-gap-9
#66Mitochondrial-Lysosomal Contact Site EngineeringRAB7A0.430$0.44sda-2026-04-01-gap-0
#67Lysosomal Positioning Dynamics ModulationLAMP10.430$0.44sda-2026-04-01-gap-0
#68Glycine-Rich Domain Competitive InhibitionTARDBP0.429$0.44sda-2026-04-01-gap-0
#69R-Loop Resolution Enhancement TherapySETX0.428$0.44sda-2026-04-01-gap-v
#70Multi-Modal CRISPR Platform for Simultaneous Editing and MonitoringDisease-causing mutations with integrated reporters0.423$0.43SDA-2026-04-03-gap-c
#71Flotillin-1 Stabilization CompoundsFLOT10.422$0.43SDA-2026-04-01-gap-l
#72HSP70 Co-chaperone DNAJB6 Universal Cross-Seeding InhibitorDNAJB60.420$0.43sda-2026-04-01-gap-9
#73PINK1/Parkin-Independent Mitophagy Bypass for Enhanced Donor MitochondriaBNIP3/BNIP3L0.418$0.43sda-2026-04-01-gap-2
#74VCP-Mediated Autophagy EnhancementVCP0.415$0.42SDA-2026-04-04-gap-t
#75Microbiome-Derived Tryptophan Metabolite NeuroprotectionAHR, IL10, TGFB10.408$0.42SDA-2026-04-01-gap-2
#76Palmitoylation-Targeted BACE1 Trafficking DisruptorsBACE10.407$0.42SDA-2026-04-01-gap-l
#77Partial Neuronal Reprogramming via Modified Yamanaka CocktailOCT40.399$0.41SDA-2026-04-04-gap-e
#78Ephrin-B2/EphB4 Axis ManipulationEPHB40.399$0.41sda-2026-04-01-gap-0
#79The Mitochondrial-Lysosomal Metabolic Coupling DysfunctionTFEB0.398$0.41SDA-2026-04-02-gap-v
#80TFEB-PGC1α Mitochondrial-Lysosomal DecouplingTFEB0.398$0.41SDA-2026-04-03-gap-a
#81The Glial Ketone Metabolic Shunt HypothesisHMGCS20.398$0.41SDA-2026-04-02-gap-v
#82SIRT6-NAD+ Axis Enhancement TherapySIRT60.395$0.40sda-2026-04-01-gap-v
#83FOXO3-Longevity Pathway Epigenetic ReprogrammingFOXO30.386$0.40sda-2026-04-01-gap-v
#84Metabolic Reprogramming via Microglial Glycolysis InhibitionHK20.385$0.39sda-2026-04-01-gap-v
#85Prohibitin-2 Mitochondrial Cross-Seeding Hub DisruptionPHB20.384$0.39sda-2026-04-01-gap-9
#86Nucleolar Stress Response NormalizationNPM10.378$0.39sda-2026-04-01-gap-v
#87Optogenetic Control of Mitochondrial Transfer NetworksChR20.378$0.39sda-2026-04-01-gap-2
#88RNA-Binding Competition Therapy for TDP-43 Cross-SeedingTARDBP0.374$0.38sda-2026-04-01-gap-9
#89Microglia-Derived Extracellular Vesicle Engineering for Targeted Mitochondrial DeliveryRAB27A/LAMP2B0.370$0.38sda-2026-04-01-gap-2
#90Extracellular Vesicle Biogenesis ModulationCHMP4B0.340$0.35SDA-2026-04-04-gap-t
#91Netrin-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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