title: Autophagic failure promotes the exocytosis and intercellular transfer of α-synuclein.
abstract: The accumulation of abnormal protein aggregates is a major characteristic of many neurodegenerative disorders, including Parkinson's disease (PD). The intracytoplasmic deposition of α-synuclein aggregates and Lewy bodies, often found in PD and other α-synucleinopathies, is thought to be linked to inefficient cellular clearance mechanisms, such as the proteasome and autophagy/lysosome pathways. The accumulation of α-synuclein aggregates in neuronal cytoplasm causes numerous autonomous changes in neurons. However, it can also affect the neighboring cells through transcellular transmission of the aggregates. Indeed, a progressive spreading of Lewy pathology among brain regions has been hypothesized from autopsy studies. We tested whether inhibition of the autophagy/lysosome pathway in α-synuclein-expressing cells would increase the secretion of α-synuclein, subsequently affecting the α-synuclein deposition in and viability of neighboring cells. Our results demonstrated that autophagic inhibition, via both pharmacological and genetic methods, led to increased exocytosis of α-synuclein. In a mixed culture of α-synuclein-expressing donor cells with recipient cells, autophagic inhibition resulted in elevated transcellular α-synuclein transmission. This increase in protein transmission coincided with elevated apoptotic cell death in the recipient cells. These results suggest that the inefficient clearance of α-synuclein aggregates, which can be caused by reduced autophagic activity, leads to elevated α-synuclein exocytosis, thereby promoting α-synuclein deposition and cell death in neighboring neurons. This finding provides a potential link between autophagic dysfunction and the progressive spread of Lewy pathology.
authors: Department of Anatomy, SMART-IABS, Konkuk University, Seoul, South Korea. hjlee@kku.ac.kr
authors: He-Jin
authors: HJ
authors: Lee
authors: Eun-Duk
authors: ED
authors: Cho
authors: Kyung Won
authors: KW
authors: Lee
authors: Jung-Hyun
authors: JH
authors: Kim
authors: Ssang-Goo
authors: SG
authors: Cho
authors: Seung-Jae
authors: SJ
authors: Lee
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D000071193:Autophagy-Related Protein 7; D002460:Cell Line; D005089:Exocytosis / Q000187:drug effects; D005110:Extracellular Space / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000378:metabolism; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D020836:Protein Structure, Quaternary; D021381:Protein Transport / Q000187:drug effects; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity
chemical_list: C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; D051844:alpha-Synuclein; C025946:3-methyladenine; D000071193:Autophagy-Related Protein 7; D000225:Adenine
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