Mechanistic description
VPS35 Retromer Restoration to Rescue Endosomal Protein Trafficking
Evidence for (5)
VPS35 mutations cause autosomal-dominant Parkinson's disease with synaptic dysfunction
Retromer protein levels are reduced in AD hippocampus and correlate with cognitive decline
Retromer dysfunction causes APP mislocalization to endosomes, increasing Aβ production
R55 compound rescues VPS35 mutations and restores retromer function in cellular models
Retromer mediates retrieval of synaptic receptors (APP, Vps10, SorLA) from degradative pathway
Evidence against (6)
VPS35 mutations cause Parkinson's, not Alzheimer's - mechanistic disconnect
VPS35 overexpression in mouse models causes dopamine neuron degeneration
Retromer enhancement increases Aβ production in some cellular models by redirecting APP to amyloidogenic compartments
R55 compound validation limited to HeLa cells and yeast; no human neuron data
Retromer affects thousands of cargo including Wntless, glutamate receptors, transferrin receptor
Correlation between VPS35 levels and cognitive decline may be secondary to neurodegeneration
Bayesian persona consensus
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