| First Author | Zhang S | Year | 2018 |
| Journal | Neurobiol Aging | Volume | 61 |
| Pages | 52-65 | PubMed ID | 29035751 |
| Mgi Jnum | J:258064 | Mgi Id | MGI:6116585 |
| Doi | 10.1016/j.neurobiolaging.2017.09.016 | Citation | Zhang S, et al. (2018) Intercellular transfer of pathogenic alpha-synuclein by extracellular vesicles is induced by the lipid peroxidation product 4-hydroxynonenal. Neurobiol Aging 61:52-65 |
| abstractText | Parkinson''s disease (PD) is characterized by accumulations of toxic alpha-synuclein aggregates in vulnerable neuronal populations in the brainstem, midbrain, and cerebral cortex. Recent findings suggest that alpha-synuclein pathology can be propagated transneuronally, but the underlying molecular mechanisms are unknown. Advances in the genetics of rare early-onset familial PD indicate that increased production and/or reduced autophagic clearance of alpha-synuclein can cause PD. The cause of the most common late-onset PD is unclear, but may involve metabolic compromise and oxidative stress upstream of alpha-synuclein accumulation. As evidence, the lipid peroxidation product 4-hydroxynonenal (HNE) is elevated in the brain during normal aging and moreso in brain regions afflicted with alpha-synuclein pathology. Here, we report that HNE increases aggregation of endogenous alpha-synuclein in primary neurons and triggers the secretion of extracellular vesicles (EVs) containing cytotoxic oligomeric alpha-synuclein species. EVs released from HNE-treated neurons are internalized by healthy neurons which as a consequence degenerate. Levels of endogenously generated HNE are elevated in cultured cells overexpressing human alpha-synuclein, and EVs released from those cells are toxic to neurons. The EV-associated alpha-synuclein is located both inside the vesicles and on their surface, where it plays a role in EV internalization by neurons. On internalization, EVs harboring pathogenic alpha-synuclein are transported both anterogradely and retrogradely within axons. Focal injection of EVs containing alpha-synuclein into the striatum of wild-type mice results in spread of synuclein pathology to anatomically connected brain regions. Our findings suggest a scenario for late-onset PD in which lipid peroxidation promotes intracellular accumulation and then extrusion of EVs containing toxic alpha-synuclein species; the EVs are then internalized by adjacent neurons, so propagating the neurodegenerative process. |
