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.
Highlights
A-Synuclein is an abundant neuronal protein that is linked to several major neurodegenerative diseases, including Parkinson’s disease (PD), dementia with Lewy bodies and multiple system atrophy; these diseases are collectively referred to as a-synucleinopathies.[1]
Genetic studies have shown that missense mutations and a multiplication of the a-synuclein gene are linked to rare forms of inherited PD, and these mutations lower the age of disease onset in carriers of the mutation.[2,3,4,5,6,7] a–Synuclein consists of 140 amino acids and is a natively unfolded protein that spontaneously develops into amyloid-like fibrils in vitro in a nucleation-dependent manner.[8]
Complexes. 3-MA inhibits the production of phosphatidylinositol-3-phosphate, which is important for autophagosome formation, inhibiting autophagy
Summary
A-Synuclein is an abundant neuronal protein that is linked to several major neurodegenerative diseases, including Parkinson’s disease (PD), dementia with Lewy bodies and multiple system atrophy; these diseases are collectively referred to as a-synucleinopathies.[1]. Genetic studies have shown that missense mutations and a multiplication of the a-synuclein gene are linked to rare forms of inherited PD, and these mutations lower the age of disease onset in carriers of the mutation.[2,3,4,5,6,7] a–Synuclein consists of 140 amino acids and is a natively unfolded protein that spontaneously develops into amyloid-like fibrils in vitro in a nucleation-dependent manner.[8] some studies have suggested that native a-synuclein is a tetrameric oligomer and that disrupting the tetrameric conformation may be critical for amyloid formation.[9] Increased expression of a-synuclein is associated with its aggregation in neuronal models, animals and humans.[10] Recent neuropathological studies have indicated that a-synuclein pathology progresses in highly specific and predictable patterns, first occurring in a few discrete regions of the lower brain stem and the olfactory bulbs and spreading into the larger areas of the brain.[11]. We observed increased transcellular transfer of a-synuclein and elevated apoptotic cell death in the recipient cells
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