| First Author | Jacquemyn J | Year | 2026 |
| Journal | Nat Cell Biol | Volume | 28 |
| Issue | 3 | Pages | 492-506 |
| PubMed ID | 41680444 | Mgi Jnum | J:392194 |
| Mgi Id | MGI:8406561 | Doi | 10.1038/s41556-026-01871-6 |
| Citation | Jacquemyn J, et al. (2026) Glucosylceramide-induced ectosomes propagate pathogenic alpha-synuclein in Parkinson's disease. Nat Cell Biol 28(3):492-506 |
| abstractText | The intercellular transmission of alpha-synuclein contributes to Parkinson's disease pathology. Yet, the mechanisms of alpha-synuclein spread are not fully understood. Here we used live-cell microscopy to examine the impact of Parkinson's disease associated lipid alterations on alpha-synuclein release. We discovered that increased glucosylceramides as a consequence of reduced beta-glucocerebrosidase activity induce ectosome shedding from primary neurons and from dopaminergic neurons derived from induced pluripotent stem cells of a patient with Parkinson's disease harbouring mutations in GBA1 (N370S, L444P and W378G) and LRRK2 (G2019S and R1441H) compared with their isogenic control. We show that elevated glucosylceramide and the pharmacological inhibition of beta-glucocerebrosidase similarly increase vesicle release and uptake by other neurons in mouse brains. Finally, we show that ectosomes are loaded with alpha-synuclein and lead to the transmission of alpha-synuclein pathology to neighbouring neurons. These data reveal ectosomes as a major route for alpha-synuclein transmission in Parkinson's disease. |
