Glucosylceramide Accumulation from GCase Deficiency Disrupts SNX5-Mediated Retr…

GCase deficiency in PD-linked GBA1 mutations leads to progressive glucosylceramide (GlcCer) accumulation in lysosomal membranes, fundamentally altering their biophysical properties. GlcCer preferentially localizes to ordered lipid domains (lipid rafts), which are precisely the membrane microdomains required for SNX5 (sorting nexin 5) association with the retromer complex. SNX5 serves as a critical bridge between the VPS35-VPS29-VPS26 trimer and phosphoinositide-specific membranes, mediating the formation of retromer-coated tubules essential for retrieving lysosomal membrane proteins, including LAMP2A and GCase itself. When GlcCer accumulation exceeds 15 mol% of total lysosomal lipid (measured by mass spectrometry in GBA1 p.N370S fibroblasts), the ordered domains become destabilized, SNX5 dissociates from membranes, and retromer function collapses. This creates a feedforward loop: GCase deficiency causes GlcCer accumulation, which disrupts SNX5 recruitment, which impairs retromer function, which reduces GCase trafficking, further reducing GCase activity. The affected membrane domains also fail to concentrate SNCA for degradation, allowing monomeric SNCA to partition into these expanded GlcCer domains where it nucleates into toxic oligomers. The prediction is that GBA1 chaperone therapy (e.g., ambroxol) will reduce GlcCer below the critical threshold and restore SNX5 membrane association. Cryo-electron tomography of patient-derived lysosomes will visualize the loss of retromer tubules correlated with GlcCer content.

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.