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TBK1 Loss Triggers Astrocyte-to-Neuron Senescence Propagatio (TBK1 → NF-κB / IRF3 / p62-autophagy / SASP effectors) — 0.00 eIF2α Phosphorylation Imbalance Disrupts Mitochondrial Prote (EIF2S1,eIF2α,PERK,GCN2,ATF4,TOMM20,TIMM23,NDUFS1,NDUFS3,COX4I1,COX5A,mitochondrial protein import) — 0.00 TBK1 Loss Triggers eIF2α-Mediated Translational Repression T (TBK1, EIF2S1) — 0.00 Closed-loop transcranial focused ultrasound targeting EC-II (SST) — 0.97 GluN2B-Mediated Thalamocortical Control of Glymphatic Tau Cl (GRIN2B) — 0.96 Closed-loop optogenetic targeting PV interneurons to restore (PVALB) — 0.96 Plasma NfL Elevation Secondary to BBB-Associated Transport D (NEFL) — 0.94 Gamma entrainment therapy to restore hippocampal-cortical sy (SST) — 0.92 Closed-loop transcranial focused ultrasound to restore hippo (CCK) — 0.91 Gut Microbiome Remodeling to Prevent Systemic NLRP3 Priming (NLRP3, CASP1, IL1B, PYCARD) — 0.91 eIF2α Phosphorylation Imbalance Creates Integrated Stress Re (EIF2S1,eIF2α,PERK,GCN2,ATF4,ATF5,CHOP,DDIT3,integrated stress response,protein synthesis) — 0.90 Hypothesis 4: Metabolic Coupling via Lactate-Shuttling Colla (SLC16A1, SLC16A7, LDHA, PDHA1) — 0.89 SIRT1-Mediated Reversal of TREM2-Dependent Microglial Senesc (SIRT1) — 0.89 TREM2-Mediated Astrocyte-Microglia Crosstalk in Neurodegener (TREM2) — 0.89 ACSL4-Driven Ferroptotic Priming in Disease-Associated Micro (ACSL4) — 0.89 Multi-Target Hypothesis: Aβ-Induced Cholinergic Damage is Pa (APP/PSEN1 (Aβ production), CHAT (cholinergic synthesis)) — 0.89 Optimized Temporal Window for Metabolic Boosting Therapy Det (IFNG) — 0.89 TREM2-APOE Axis Dissociation for Selective DAM Activation (TREM2-APOE axis) — 0.89 Hippocampal CA3-CA1 synaptic rescue via DHHC2-mediated PSD95 (BDNF) — 0.89 p38α Inhibitor and PRMT1 Activator Combination to Restore Ph (MAPK14/PRMT1) — 0.88 TBK1 Loss Locks Microglia in an Aged/Senescent Transcription (TBK1 → NF-κB / IRF3 / p62-autophagy / cGAS-STING axis) — 0.88 APOE-Dependent Autophagy Restoration (MTOR) — 0.88 Closed-loop tACS targeting EC-II parvalbumin interneurons to (PVALB) — 0.87 RBM45 Liquid-Liquid Phase Separation Dominance Hijacks RNA P (RBM45,GSK3B,TDP-43,TARDBP,hnRNP A1,HNRNPA1,phase separation,Liquid droplet) — 0.87 Complement Cascade Inhibition Synaptic Protection (%s) — 0.87 Optogenetic restoration of hippocampal gamma oscillations vi (PVALB) — 0.87 Gamma Oscillation Entrainment Enhances lncRNA-9969-Mediated (PVALB, CREB1, lncRNA-9969, neuronal autophagy pathway) — 0.87 Glymphatic-Mediated Tau Clearance Dysfunction (MAPT) — 0.86 Beta-frequency entrainment therapy targeting PV interneuron- (SST) — 0.86 SFPQ Paralog Displacement Triggers Cryptic Polyadenylation a (SFPQ,NONO,PSP1,TARDBP,poly(A) machinery,CPSF,PABPN1) — 0.86
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× GBA1-Deficiency Disrupts × PD-Associated GWAS Varian
GBA1 · neurodegeneration · mechanistic
Composite 0.747
Price $0.50
Evidence For 0
Evidence Against 0
GBA1 deficiency leads to glucosylceramide accumulation in the inner mitochondrial membrane (as shown by lipidomics of patient fibroblasts), which directly stabilizes Miro1 protein levels by inhibiting the mitochondrial protease LONP1. Miro1 is a calcium-sensitive adaptor that tethers mitochondria to the microtubule motor complex; under normal conditions, Miro1 is ubiquitinated by the Pink1-Parkin pathway and degraded to enable mitophagosome formation. When GlcCer stabilizes Miro1, damaged mitoch
GBA1 · neurodegeneration · mechanistic
Composite 0.743
Price $0.50
Evidence For 0
Evidence Against 0
Recent 2024 PD GWAS has identified significant associations in the cathepsin genes CTSO (cathepsin O) and CTSF (cathepsin F), suggesting that non-lysosomal cathepsin variants modify PD risk. CTSO is a cysteine protease with structural similarity to cathepsin B, while CTSF is a lysosomal cysteine protease with overlapping substrate specificity with cathepsin L. We propose that PD risk alleles in CTSO/CTSF create subtle shifts in the intracellular cathepsin network that become catastrophic only in
Convergent vs Divergent Predictions
This summary checks where the selected hypotheses point toward the same target or mechanism, and where they pull in opposite directions.
GBA1 Inter Organelle Crosstalk Lysosomal Stress neurodegeneration
Convergent signals
GBA1 recurs across 2 selected hypotheses with aligned directionality in inter organelle crosstalk, lysosomal stress.
Divergent signals
No direct polarity conflicts detected among the selected hypotheses.
Verdict Summary 3/11
dimensions won
GBA1-Deficiency Disrupts Mitochondrial-
2/11
dimensions won
PD-Associated GWAS Variants in CTSO and
Radar Chart — 10 Dimensions
Score Breakdown
Dimension GBA1-Deficiency Disrupts Mitoc PD-Associated GWAS Variants in Mechanistic 0.740 0.700 Evidence 0.680 0.580 Novelty 0.820 0.950 Feasibility 0.000 0.000 Impact 0.000 0.000 Druggability 0.000 0.000 Safety 0.000 0.000 Competition 0.000 0.000 Data 0.000 0.000 Reproducible 0.000 0.000 KG Connect 0.500 0.500
Evidence GBA1-Deficiency Disrupts Mitochondrial- Lysosomal Contact Si No evidence citations yet
PD-Associated GWAS Variants in CTSO and CTSF Genes Create a No evidence citations yet
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