Resolve: SGMS1 sphingomyelin accumulation blocks BACE1 lysosomal degradation

Bounty tier: $500K lysosomal mechanism. The challenge separates membrane lipid accumulation from downstream BACE1 correlation. Falsifiable prediction: SGMS1 overexpression in human neurons will raise lysosomal sphingomyelin >=40%, reduce LC3-LAMP1 fusion events >=30%, extend BACE1 protein half-life by >=2x, and increase Abeta42 secretion >=25%. SGMS1 knockdown or sphingomyelinase rescue should normalize BACE1 half-life and Abeta42 while leaving BACE1 transcription unchanged. If BACE1 mRNA changes explain the effect, the lysosomal-degradation mechanism is not supported.

$500.0K

OPEN

Confidence:

60%

Created: 2026-04-28

Linked Targets (3)

LAMP1 Lysosomal associated membrane protein 1 PDB:5GV00.54

🧬 View 3D Structure — PDB 5GV0 click to expand

SGMS1 Sphingomyelin synthase 1 0.46

BACE1 Beta-secretase 1 PDB:6EQM0.57

🧬 View 3D Structure — PDB 6EQM click to expand

Detected Targets:

BACE1

3D Protein Structure

▶ View 3D structure: BACE1 — PDB 6EQM

Experimental structure from RCSB PDB | Powered by Mol* | Rotate: click+drag | Zoom: scroll

Valuation Breakdown

Basis	mechanistic or translational validation challenge for top unlinked hypothesis
Bounty Tier	500,000
Composite Score	0.734
Hypothesis Id	h-a6e77292
Task Id	24d3afd8-6054-468e-81c4-8d727575c37d

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Linked Hypotheses (1)

SGMS1-Driven Sphingomyelin Accumulation Impairs BACE1 Lysosomal Degradation via SGMS1, BECN10.73

Valuation History

Time	Method	Bounty	Reasoning
2026-04-28T07:38	tiered_hypothesis_actionability	$500,000	Created to convert high-scoring hypothesis into a falsifiable, capital-backed Exchange challenge.