Exp Mol Med.
2013 May;45(5):e22.
Autophagic failure promotes the exocytosis and intercellular transfer of alpha-synuclein
- Affiliations
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- 1Department of Anatomy, Konkuk University, Seoul, South Korea. hjlee@kku.ac.kr
- 2SMART-IABS, Konkuk University, Seoul, South Korea. sjlee@konkuk.ac.kr
- 3Department of Animal Biotechnology and Animal Resources Research Center, Konkuk University, Seoul, South Korea.
- 4Department of Biomedical Science and Technology, Konkuk University, Seoul, South Korea.
Abstract
- The accumulation of abnormal protein aggregates is a major characteristic of many neurodegenerative disorders, including Parkinson's disease (PD). The intracytoplasmic deposition of alpha-synuclein aggregates and Lewy bodies, often found in PD and other alpha-synucleinopathies, is thought to be linked to inefficient cellular clearance mechanisms, such as the proteasome and autophagy/lysosome pathways. The accumulation of alpha-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 alpha-synuclein-expressing cells would increase the secretion of alpha-synuclein, subsequently affecting the alpha-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 alpha-synuclein. In a mixed culture of alpha-synuclein-expressing donor cells with recipient cells, autophagic inhibition resulted in elevated transcellular alpha-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 alpha-synuclein aggregates, which can be caused by reduced autophagic activity, leads to elevated alpha-synuclein exocytosis, thereby promoting alpha-synuclein deposition and cell death in neighboring neurons. This finding provides a potential link between autophagic dysfunction and the progressive spread of Lewy pathology.
MeSH Terms
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Adenine/analogs & derivatives/pharmacology
Animals
*Autophagy/drug effects
Cell Line
*Exocytosis/drug effects
Extracellular Space/*metabolism
Humans
Mice
Mice, Knockout
Microtubule-Associated Proteins/deficiency/metabolism
Phagosomes/drug effects/metabolism
Protein Structure, Quaternary
Protein Transport/drug effects
alpha-Synuclein/chemistry/*metabolism/secretion/toxicity
Microtubule-Associated Proteins
alpha-Synuclein
Adenine
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