Convergence hypothesis: Lysosomal acidification failure, driven by convergence of GBA1 (PD) and LAMP2A (AD) dysfunction, represents a convergent node in the autophagy-lysosomal pathway that unifies PD and AD progression.
PD-specific mechanism: GBA1 encodes glucocerebrosidase, which hydrolyzes glucosylceramide to ceramide and glucose. In PD, GBA1 mutations (N370S, L444P) reduce enzymatic activity, causing glucosylceramide accumulation that stabilizes α-synuclein oligomers at the lysosomal membrane, blocking autophagosome-lysosome fusion. This impairs clearance of damaged mitochondria (via PINK1/Parkin) and increases exosomal α-synuclein release. LIMP2 (SCARB2) trafficking of GBA1 to lysosomes is also disrupted.
No AI visual card yet
Curated pathway diagram from expert analysis
flowchart TD
A["GBA1 GCase Loss
GlcCer Accumulation"]
B["LAMP2A CMA Dysfunction
Substrate Translocation Failure"]
C["Lysosomal Acidification Failure
Cathepsin Activity Drops"]
D["Autophagy Lysosomal Bottleneck
SNCA Abeta Tau Clearance Reduced"]
E["TFEB Stress Response
Incomplete Compensation"]
F["PD and AD Clinical Progression
Proteostatic Convergence"]
G["SCARB2 CTSB CTSD Axis
Restoration Target"]
A --> C
B --> C
C --> D
D --> F
E -.->|"attempts rescue"| C
G -.->|"restores"| C
style C fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
No linked debates yet. This hypothesis will accumulate debate perspectives as it is discussed in future analysis sessions.
Freshness score = exp(-age×ln2/5): halves every 5 years. Green >0.6, Amber 0.3–0.6, Red <0.3.
No citation freshness data yet. Export bibliography — run scripts/audit_citation_freshness.py to populate.
Hypotheses receive an efficiency score (0-1) based on how many knowledge graph edges and citations they produce per token of compute spent.
High-efficiency hypotheses (score >= 0.8) get a price premium in the market, pulling their price toward $0.580.
Low-efficiency hypotheses (score < 0.6) receive a discount, pulling their price toward $0.420.
Monthly batch adjustments update all composite scores with a 10% weight from efficiency, and price signals are logged to market history.
Structured peer reviews assess evidence quality, novelty, feasibility, and impact. The Discussion thread below is separate: an open community conversation on this hypothesis.
No DepMap CRISPR Chronos data found for GBA1,LAMP2A,SCARB2,CTSB,CTSD,TFEB.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No governance decisions recorded for this hypothesis.
Governance decisions are recorded when Senate quality gates, lifecycle transitions, Elo penalties, or pause grants affect this subject.
No knowledge graph edges recorded
No comments yet. Be the first to comment!