|
KMID : 0620920130450050004
|
|
Experimental & Molecular Medicine
2013 Volume.45 No. 5 p.4 ~ p.0
|
|
|
Autophagic failure promotes the exocytosis and intercellular transfer of α-synuclein
|
|
Lee He-Jin
Cho Eun-Duk
Lee Kyung-Won
Kim Jung-Hyun
Cho Ssang-Goo
Lee Seung-Jae
|
|
|
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.
|
|
|
KEYWORD
|
|
|
autophagy, neurodegeneration, protein aggregation, signal transduction
|
|
|
FullTexts / Linksout information
|
|
|
|
|
|
Listed journal information
|
|
    
|
|