Synaptic-Selective Autophagy Receptor Expression to Bypass Axonal Lysosome Deficiency

From Analysis:

Quantitative proteomics of the aging synapse: protein turnover and aggregation in neurodegeneration

How does synaptic protein turnover change with age and neurodegeneration, and what role does impaired protein homeostasis play in synaptic dysfunction? Specifically, how do ubiquitin-proteasome and autophagy-lysosome pathways fail in aging synapses, leading to accumulation of misfolded proteins and synaptic degeneration in Alzheimer's and related dementias?

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Hypotheses from Same Analysis (6)

These hypotheses emerged from the same multi-agent debate that produced this hypothesis.

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graph TD
    TFEB["TFEB"] -->|transcription fact| lysosomal_biogenesis["lysosomal_biogenesis"]
    TFEB_1["TFEB"] -->|transcription fact| V_ATPase["V-ATPase"]
    TFEB_2["TFEB"] -->|transcription fact| cathepsins["cathepsins"]
    mTOR["mTOR"] -->|hyperactive in| AD_brain["AD_brain"]
    mTOR_3["mTOR"] -->|phosphorylates| TFEB_Ser211["TFEB_Ser211"]
    A__oligomers["Aβ_oligomers"] -->|accumulates at| synaptic_terminals["synaptic_terminals"]
    phosphorylated_tau["phosphorylated_tau"] -->|accumulates at| synaptic_terminals_4["synaptic_terminals"]
    USP14["USP14"] -->|associated with| n19S_proteasome["19S_proteasome"]
    USP14_5["USP14"] -->|removes ubiquitin| proteasome_substrates["proteasome_substrates"]
    ubiquitinated_proteins["ubiquitinated_proteins"] -->|accumulates in| AD_hippocampus["AD_hippocampus"]
    BAG3["BAG3"] -->|interacts with| p62_SQSTM1["p62/SQSTM1"]
    BAG3_6["BAG3"] -->|recruits Hsc70 cli| autophagosomes["autophagosomes"]
    style TFEB fill:#ce93d8,stroke:#333,color:#000
    style lysosomal_biogenesis fill:#4fc3f7,stroke:#333,color:#000
    style TFEB_1 fill:#ce93d8,stroke:#333,color:#000
    style V_ATPase fill:#ce93d8,stroke:#333,color:#000
    style TFEB_2 fill:#ce93d8,stroke:#333,color:#000
    style cathepsins fill:#ce93d8,stroke:#333,color:#000
    style mTOR fill:#ce93d8,stroke:#333,color:#000
    style AD_brain fill:#4fc3f7,stroke:#333,color:#000
    style mTOR_3 fill:#ce93d8,stroke:#333,color:#000
    style TFEB_Ser211 fill:#4fc3f7,stroke:#333,color:#000
    style A__oligomers fill:#4fc3f7,stroke:#333,color:#000
    style synaptic_terminals fill:#4fc3f7,stroke:#333,color:#000
    style phosphorylated_tau fill:#4fc3f7,stroke:#333,color:#000
    style synaptic_terminals_4 fill:#4fc3f7,stroke:#333,color:#000
    style USP14 fill:#ce93d8,stroke:#333,color:#000
    style n19S_proteasome fill:#4fc3f7,stroke:#333,color:#000
    style USP14_5 fill:#ce93d8,stroke:#333,color:#000
    style proteasome_substrates fill:#4fc3f7,stroke:#333,color:#000
    style ubiquitinated_proteins fill:#4fc3f7,stroke:#333,color:#000
    style AD_hippocampus fill:#4fc3f7,stroke:#333,color:#000
    style BAG3 fill:#ce93d8,stroke:#333,color:#000
    style p62_SQSTM1 fill:#ce93d8,stroke:#333,color:#000
    style BAG3_6 fill:#ce93d8,stroke:#333,color:#000
    style autophagosomes fill:#ce93d8,stroke:#333,color:#000

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