VPS35 is the core scaffolding component of the retromer complex, a multimeric protein machinery that mediates selective retrieval of transmembrane cargo from endosomes back to the trans-Golgi network (TGN) or plasma membrane[1]. As the largest retromer subunit, VPS35 provides the structural framework for cargo recognition and coordinates the recruitment of accessory proteins that drive vesicle formation and trafficking[2].
Mutations in VPS35 are linked to autosomal dominant late-onset Parkinson's disease, making it one of the rarer monogenic PD genes with clear mechanistic relevance to sporadic disease[3].
VPS35 is a 796-amino acid protein that forms a stable heterotrimeric complex with VPS26 and VPS29. The structure consists of:
The retromer coats the cytoplasmic face of endosomes, selecting cargo proteins for retrieval to the TGN or plasma membrane[4].
The retromer complex functions in:
VPS35/retromer traffics several proteins central to neurodegenerative disease:
The most well-characterized VPS35 mutation is D620N (asparagine at position 620 substituted for aspartate), which causes autosomal dominant late-onset Parkinson's disease[3:1]. This mutation:
The D620N mutation affects retromer function through several mechanisms[6]:
VPS35 intersects with several major Parkinson's disease genes:
Even without VPS35 mutations, retromer function declines with age and is impaired in sporadic Parkinson's disease[7]. This age-related decline may:
Retromer function can be enhanced pharmacologically:
Several strategies are being explored:
Seaman MN. The retromer complex: from yeast to human. Traffic. 2012. ↩︎
Bhalla A, et al. The location and trafficking routes of the neuronal retromer. Brain Res Bull. 2012. ↩︎
Zimprich A, et al. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am J Hum Genet. 2011. ↩︎ ↩︎
McGough IJ, et al. Retromer stability depends on the ESCRT machinery. Nature. 2024. ↩︎
Moceri S, et al. Retromer deficiency in tauopathy and Alzheimer's disease: therapeutic implications. Acta Neuropathol. 2021. ↩︎
Tang FL, et al. VPS35 D620N knockin mice recapitulate core features of Parkinson's disease. Neuron. 2020. ↩︎
Zhang Y, et al. Retromer in neurodegenerative diseases: dysfunction and beyond. Neurobiol Dis. 2023. ↩︎