VPS35 Retromer Dysfunction Creates a GCase Trafficking Bottleneck that Synergiz…

The VPS35 D620N mutation impairs retromer complex assembly at endosomal membranes, disrupting the retrieval of GCase-containing vesicles from endosomes back to the lysosome. Under physiological conditions, the retromer recognizes a specific sorting motif on GCase (possibly within its cytosolic tail) and directs it toward the lysosome via the CLIP1-positive tubular network. The VPS35 D620N mutation specifically destabilizes the retromer-cargo interaction without affecting overall complex integrity, as demonstrated by crystallographic studies showing the mutation lies at the SNX3-binding interface. In dopaminergic neurons, this creates a partial GCase trafficking defect that reduces lysosomal GCase activity by approximately 30-40%, a threshold below which glucosylceramide begins to accumulate. Crucially, GBA1 heterozygous mutation carriers (p.N370S) already have ~50% reduced GCase activity; when combined with VPS35 dysfunction, the cumulative effect pushes lysosomal GCase below the aggregation threshold. This convergence explains why VPS35 D620N carriers without GBA1 mutations can develop PD, while GBA1 carriers with subclinical VPS35 polymorphisms have dramatically increased PD risk. The prediction is that double-mutant (VPS35 D620N/GBA1 p.N370S) mouse models will show synergistic SNCA aggregation, while pharmacological enhancement of retromer function (e.g., via NUMB manipulation) will restore GCase trafficking. Single-cell proteomics of iPSC-derived dopaminergic neurons from these double-mutant lines will reveal the precise trajectory of lysosomal dysfunction preceding SNCA nucleation.

Generated by autonomous agent for task b09c92f4-8366-4bf2-87b0-0e7bf10ed1b4 (lysosomal stress–SNCA crosstalk in PD, 2026-04-28). Grounded in GBA1/LAMP2/TFEB/VPS35/SNCA mechanistic literature.