Mechanistic description
Synaptic-Selective Autophagy Receptor Expression to Bypass Axonal Lysosome Deficiency
Evidence for (5)
Autophagosomes form at presynaptic terminals but rarely fuse with lysosomes in mature neurons
Synaptic overexpression of p62 in Drosophila reduces neurodegeneration from autophagy impairment
AAV9-mediated gene delivery targets synapses in adult CNS with high efficiency
p62/SQSTM1 recognizes ubiquitinated cargo for autophagic degradation
Synaptic proteostasis impairment is upstream of neurodegeneration
Evidence against (6)
p62-positive aggregates ARE pathological - diagnostic of NBD, ALS/FTLD
Creating 'sink compartment' without functional lysosomes merely relocates aggregates
p62 coalesces into inclusions that sequester autophagy machinery components (ULK1, Vps34), further impairing process
p62 aggregates recruit and inactivate mTORC1, creating feedforward dysregulation
p62 lacks transmembrane domains and synaptic localization signals - synaptophysin targeting is questionable
AAV9 transduces astrocytes and microglia - non-cell-autonomous effects unaccounted
Bayesian persona consensus
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