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J-protein substrate specificity codes enable HSP70 discrimin (DNAJB6) — 0.00 LDLR-Primed LRP1 Transcytosis with pH-Responsive Escape Stra (LDLR) — 0.00 HSP90-cochaperone complexes preferentially stabilize interme (HSP90AA1, HSP90AB1, STIP1, AHSA1) — 0.00 Alpha-theta entrainment therapy to enhance default mode netw (SST) — 0.00 Closed-loop transcranial focused ultrasound to restore hippo (SST) — 0.00 J-protein co-chaperone system mediates selective autophagy t (DNAJB6, DNAJB2, HSPA8, HSPA1A, MAP1LC3B, ATG7) — 0.00 H6-V1: Aberrant eIF2α Phosphorylation Drives Mitochondrial T (EIF2S1, EIF2AK3/PERK, PPP1R15B, EIF2B, MRPL12, MRPS18B, TUFM) — 0.00 LAMP1 Overexpression to Enhance Lysosomal Capacity Independe (LAMP1) — 0.00 Closed-loop transcranial focused ultrasound with gamma entra (PVALB) — 0.00 CREB-Dependent Differential Complement Regulator Positioning (CREB1, CD55, CD46) — 0.00 LAMP2A Upregulation to Enhance Chaperone-Mediated Autophagy (LAMP2A) — 0.00 TBK1 Loss Triggers eIF2α-Mediated Translational Repression T (TBK1, EIF2S1) — 0.00 GLUT1-Mediated Carrier-Conjugate Delivery Strategy (LDLR) — 0.00 CYP46A1-Mediated Cholesterol Reduction Prevents eIF2α-Driven (CYP46A1) — 0.00 Cell-Type-Specific TFEB Modulation Combined with Trehalose f (TFEB) — 0.00 CYP46A1 Small Molecule Activator Therapy (CYP46A1) — 0.00 Activity-Dependent CD55/CD46 Trafficking and Synaptic Surfac (CD55 (DAF), CD46 (MCP)) — 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 Astrocyte-to-Neuron Senescence Propagatio (TBK1 → NF-κB / IRF3 / p62-autophagy / SASP effectors) — 0.00 LDLR-Mediated Neurosteroid Precursor Delivery Strategy (LDLR) — 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
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× PD-Associated GWAS Varian × GBA1-Deficiency Disrupts
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
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
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 2/11
dimensions won
PD-Associated GWAS Variants in CTSO and
3/11
dimensions won
GBA1-Deficiency Disrupts Mitochondrial-
Radar Chart — 10 Dimensions
Score Breakdown
Dimension PD-Associated GWAS Variants in GBA1-Deficiency Disrupts Mitoc Mechanistic 0.700 0.740 Evidence 0.580 0.680 Novelty 0.950 0.820 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 PD-Associated GWAS Variants in CTSO and CTSF Genes Create a No evidence citations yet
GBA1-Deficiency Disrupts Mitochondrial- Lysosomal Contact Si No evidence citations yet
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