Abstract
Autophagy is a pivotal intracellular process by which cellular macromolecules are degraded upon various stimuli. A failure in the degradation of autophagic substrates such as impaired organelles and protein aggregates leads to their accumulations, which are characteristics of many neurodegenerative diseases. Pharmacological activation of autophagy has thus been considered a prospective therapeutic approach for treating neurodegenerative diseases. Among a number of autophagy-inducing agents, trehalose has received attention for its beneficial effects in different disease models of neurodegeneration. However, how trehalose promotes autophagy has not been fully revealed. We investigated the influence of trehalose and other disaccharides upon autophagic flux and aggregation of α-synuclein, a protein linked to Parkinson's disease. In differentiated human neuroblastoma and primary rat cortical neuron culture models, treatment with trehalose and other disaccharides resulted in accumulation of lipidated LC3 (LC3-II), p62, and autophagosomes, whereas it decreased autolysosomes. On the other hand, addition of Bafilomycin A1 to trehalose treatments had relatively marginal effect, an indicative of autophagic flux blockage. In concordance with these results, the cells treated with trehalose exhibited an incremental tendency in α-synuclein aggregation. Secretion of α-synuclein was also elevated in the culture medium upon trehalose treatment, thereby significantly increasing intercellular transmission of this protein. Despite the substantial increase in α-synuclein aggregation, which normally leads to cell death, cell viability was not affected upon treatment with trehalose, suggesting an autophagy-independent protective function of trehalose against protein aggregates. This study demonstrates that, although trehalose has been widely considered an autophagic inducer, it may be actually a potent blocker of the autophagic flux.
Highlights
Autophagy is an essential cellular process that disposes of dysfunctional or superfluous organelles and proteins through lysosomes.[1]
The amyloid fibril form of α-synuclein is a crucial component of Lewy bodies, the major pathological intracytoplasmic inclusion typically observed in synucleinopathies. α-Synuclein consists of 140 amino acids and is a natively unfolded protein that spontaneously develops into amyloid fibrils.[9]
Autophagic marker LC3-II and autophagy substrate p62 proteins were examined (Figure 1a). p62 protein increased more than sixfold in trehalose-treated and threefold in sucrose-treated cells, but were not changed in cells treated with sorbitol or mannose
Summary
Autophagy is an essential cellular process that disposes of dysfunctional or superfluous organelles and proteins through lysosomes.[1]. Α-Synuclein consists of 140 amino acids and is a natively unfolded protein that spontaneously develops into amyloid fibrils.[9] In the neuronal cells of both cellular and animal models, the α-synuclein is aggregated and secreted via unconventional exocytosis under various stress conditions.[10,11,12] In PD, Lewy body pathology spreads through a highly specific and predictable pattern in the brain; αsynuclein aggregation appears in a few discrete regions of the lower brain stem and the olfactory bulbs, whereas in the later stage it disseminates to larger brain areas.[13]. Our previous study has shown that the autophagic dysfunction induced by pharmacological inhibitors or autophagy gene (ATG7) deficiency resulted in the accumulation of α-synuclein aggregates in vesicle fractions and increased exocytosis of α-synuclein.[12] Under the same conditions of autophagic dysfunction, we observed augmentations in both transcellular transfer of α-synuclein and cell death in the recipient cells
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