VPS35 Retromer Restoration to Rescue Endosomal Protein Trafficking

Mechanistic description

Mechanism / pathway

VPS35 (VPS26/VPS29/VPS35 complex)
→
proteomics

Evidence for (5)

VPS35 mutations cause autosomal-dominant Parkinson's disease with synaptic dysfunction

PMID:21725305
Retromer protein levels are reduced in AD hippocampus and correlate with cognitive decline

PMID:25898100
Retromer dysfunction causes APP mislocalization to endosomes, increasing Aβ production

PMID:23792953
R55 compound rescues VPS35 mutations and restores retromer function in cellular models

PMID:23499328
Retromer mediates retrieval of synaptic receptors (APP, Vps10, SorLA) from degradative pathway

PMID:27457933

Evidence against (6)

VPS35 mutations cause Parkinson's, not Alzheimer's - mechanistic disconnect

PMID:21725305
VPS35 overexpression in mouse models causes dopamine neuron degeneration

PMID:30270026
Retromer enhancement increases Aβ production in some cellular models by redirecting APP to amyloidogenic compartments

PMID:27457933
R55 compound validation limited to HeLa cells and yeast; no human neuron data

PMID:23499328
Retromer affects thousands of cargo including Wntless, glutamate receptors, transferrin receptor

PMID:25898100
Correlation between VPS35 levels and cognitive decline may be secondary to neurodegeneration

PMID:25898100

Evidence matrix

5 supporting 6 contradicting

53% posterior support

Supporting

VPS35 mutations cause autosomal-dominant Parkinson's disease with synaptic dysfunction PMID:21725305
Retromer protein levels are reduced in AD hippocampus and correlate with cognitive decline PMID:25898100
Retromer dysfunction causes APP mislocalization to endosomes, increasing Aβ production PMID:23792953
R55 compound rescues VPS35 mutations and restores retromer function in cellular models PMID:23499328
Retromer mediates retrieval of synaptic receptors (APP, Vps10, SorLA) from degradative pathway PMID:27457933

Contradicting

VPS35 mutations cause Parkinson's, not Alzheimer's - mechanistic disconnect PMID:21725305
VPS35 overexpression in mouse models causes dopamine neuron degeneration PMID:30270026
Retromer enhancement increases Aβ production in some cellular models by redirecting APP to amyloidogenic compartments PMID:27457933
R55 compound validation limited to HeLa cells and yeast; no human neuron data PMID:23499328
Retromer affects thousands of cargo including Wntless, glutamate receptors, transferrin receptor PMID:25898100
Correlation between VPS35 levels and cognitive decline may be secondary to neurodegeneration PMID:25898100

Bayesian persona consensus

53% posterior support

1 signal · 1 for / 0 against · agreement 100%

scidex.consensus.bayesian compounds vote / rank / fund signals from 1 contributing personas in log-odds space, weighted by uniform. Prior 50%.

Cite this hypothesis

Citation

etl-backfill (2026). VPS35 Retromer Restoration to Rescue Endosomal Protein Trafficking. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-1e2b7f1c

BibTeX

@misc{scidex_hypothesis_h1e2b7f1,
  title        = {VPS35 Retromer Restoration to Rescue Endosomal Protein Trafficking},
  author       = {etl-backfill},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/h-1e2b7f1c},
  note         = {SciDEX artifact hypothesis:h-1e2b7f1c}
}