Hsp70 cochaperone BAG3-mediated Autophagy Activation for Synaptic Protein Quality Control

BAG3 (Bcl-2-associated athanogene 3) proteomics market 45% proposed
Composite
45%
Novelty
65%
Feasibility
40%
Impact
55%
Mechanistic
55%
Druggability
35%
Safety
40%
Confidence
47%

Mechanistic description

Hsp70 cochaperone BAG3-mediated Autophagy Activation for Synaptic Protein Quality Control

Evidence for (5)

  • BAG3 overexpression enhances clearance of ubiquitinated aggregates via selective autophagy

    PMID:24662967

  • BAG3 directly interacts with p62/SQSTM1 to bridge Hsc70 clients to autophagosomes

    PMID:26364927

  • BAG3 expression decreases with aging in neurons and in AD brain tissue

    PMID:29999487

  • p62/SQSTM1 accumulates in AD synapses, suggesting upstream autophagy receptor saturation

    PMID:30401736

  • BAG3-Hsc70-p62 axis directs substrates from proteasome to autophagy

    PMID:26364927

Evidence against (6)

  • BAG3 is primarily a stress-response protein - elevating in non-stressed synapses may be counterproductive

    PMID:26240158

  • Forced BAG3 overexpression causes Hsc70 sequestration, impairing general proteostasis

    PMID:26240158

  • BAG3 implicated in propagating tau pathology through exosome secretion

    PMID:31988307

  • p62 accumulation IS pathological - p62-positive inclusions are diagnostic of NBD and seen in ALS/FTLD

    PMID:24456934

  • p62 knockout reduces tau aggregation - p62 is pathological, not therapeutic

    PMID:24456934

  • p62 accumulates in AD synapses because lysosomal degradation is impaired - enhancing BAG3 won't fix lysosomes

    PMID:30401736