Autophagic failure promotes the exocytosis and intercellular transfer of alpha-synuclein.
- Author:
He Jin LEE
1
;
Eun Duk CHO
;
Kyung Won LEE
;
Jung Hyun KIM
;
Ssang Goo CHO
;
Seung Jae LEE
Author Information
1. Department of Anatomy, Konkuk University, Seoul, South Korea. hjlee@kku.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
autophagy;
neurodegeneration;
protein aggregation;
signal transduction
- MeSH:
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
- From:Experimental & Molecular Medicine
2013;45(5):e22-
- CountryRepublic of Korea
- Language:English
-
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.
