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🗣 Wd提问: vps35

🤖 Ai回答:
VPS35 (Vacuolar Protein Sorting 35) is a critical component of the retromer complex, a highly conserved protein complex involved in intracellular trafficking、Here&039;s an overview of its key aspects:

Function
Retromer Complex Role: VPS35 serves as the core subunit of the retromer, which mediates retrograde transport of cargo proteins (e.g., receptors, enzymes) from endosomes back to the trans-Golgi network or the cell membrane.
Cargo Recognition: It helps recognize and sort specific transmembrane cargo proteins (e.g., CI-M6PR, Wntless, GLUT1) for recycling, preventing their degradation in lysosomes.
Endosomal Sorting: Maintains cellular homeostasis by regulating endosomal dynamics and membrane trafficking.

Clinical Significance
1、Parkinson’s Disease (PD):
The VPS35-D620N mutation (aspartic acid to asparagine at position 620) is a rare but pathogenic autosomal dominant cause of late-onset PD.
Disrupts retromer function, leading to:
Impaired mitochondrial quality control (via disrupted mitochondrial-derived vesicle trafficking).
Accumulation of α-synuclein aggregates.
Defective autophagy and lysosomal degradation.
Associated with typical PD symptoms (tremor, rigidity) but often with slower progression.

2、Alzheimer’s Disease (AD):
Retromer dysfunction (including VPS35 deficiency) is linked to increased amyloid-β production due to altered trafficking of APP (amyloid precursor protein).
Reduced VPS35 levels observed in AD brains.

3、Other Conditions:
Implicated in lysosomal storage disorders, diabetes (via GLUT1/GLUT4 trafficking), and cancer (altered Wnt signaling).

Therapeutic Target
Retromer Stabilizers: Small molecules (e.g., R55, TPT-260) that enhance retromer assembly/function are being explored to treat PD and AD.
Gene Therapy: Experimental approaches aim to restore VPS35 expression in neurodegenerative models.

Key Interactions
Binds VPS26 and VPS29 to form the retromer cargo-selective subcomplex.
Interacts with SNX (sorting nexin) proteins for membrane deformation and tubule formation.

Research Tools
Antibodies: Anti-VPS35 antibodies (e.g., from Abcam, Cell Signaling) for Western blot/IF.
Models: *Drosophila* and mouse models with VPS35 mutations recapitulate PD-like phenotypes.

If you’re interested in a specific aspect (e.g., molecular mechanisms, disease links, or therapeutics), let me know!

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