Synaptic-Selective Autophagy Receptor Expression to Bypass Axonal Lysosome Defi…

Mechanistic description

Synaptic-Selective Autophagy Receptor Expression to Bypass Axonal Lysosome Deficiency

Mechanism / pathway

SQSTM1 (p62/sequestosome 1)
→
proteomics

Evidence for (5)

Autophagosomes form at presynaptic terminals but rarely fuse with lysosomes in mature neurons

PMID:28760822
Synaptic overexpression of p62 in Drosophila reduces neurodegeneration from autophagy impairment

PMID:25327251
AAV9-mediated gene delivery targets synapses in adult CNS with high efficiency

PMID:25369104
p62/SQSTM1 recognizes ubiquitinated cargo for autophagic degradation

PMID:24456934
Synaptic proteostasis impairment is upstream of neurodegeneration

PMID:30401736

Evidence against (6)

p62-positive aggregates ARE pathological - diagnostic of NBD, ALS/FTLD

PMID:24456934
Creating 'sink compartment' without functional lysosomes merely relocates aggregates

PMID:24456934
p62 coalesces into inclusions that sequester autophagy machinery components (ULK1, Vps34), further impairing process

PMID:24456934
p62 aggregates recruit and inactivate mTORC1, creating feedforward dysregulation

PMID:28628113
p62 lacks transmembrane domains and synaptic localization signals - synaptophysin targeting is questionable

PMID:28760822
AAV9 transduces astrocytes and microglia - non-cell-autonomous effects unaccounted

PMID:25369104

Evidence matrix

5 supporting 6 contradicting

47% posterior support

Supporting

Autophagosomes form at presynaptic terminals but rarely fuse with lysosomes in mature neurons PMID:28760822
Synaptic overexpression of p62 in Drosophila reduces neurodegeneration from autophagy impairment PMID:25327251
AAV9-mediated gene delivery targets synapses in adult CNS with high efficiency PMID:25369104
p62/SQSTM1 recognizes ubiquitinated cargo for autophagic degradation PMID:24456934
Synaptic proteostasis impairment is upstream of neurodegeneration PMID:30401736

Contradicting

p62-positive aggregates ARE pathological - diagnostic of NBD, ALS/FTLD PMID:24456934
Creating 'sink compartment' without functional lysosomes merely relocates aggregates PMID:24456934
p62 coalesces into inclusions that sequester autophagy machinery components (ULK1, Vps34), further impairing process PMID:24456934
p62 aggregates recruit and inactivate mTORC1, creating feedforward dysregulation PMID:28628113
p62 lacks transmembrane domains and synaptic localization signals - synaptophysin targeting is questionable PMID:28760822
AAV9 transduces astrocytes and microglia - non-cell-autonomous effects unaccounted PMID:25369104

Bayesian persona consensus

47% posterior support

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

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). Synaptic-Selective Autophagy Receptor Expression to Bypass Axonal Lysosome Defi…. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-e315a365

BibTeX

@misc{scidex_hypothesis_he315a36,
  title        = {Synaptic-Selective Autophagy Receptor Expression to Bypass Axonal Lysosome Defi…},
  author       = {etl-backfill},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/h-e315a365},
  note         = {SciDEX artifact hypothesis:h-e315a365}
}