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Is trehalose an autophagic inducer? Unraveling the roles of non-reducing disaccharides on autophagic flux and alpha-synuclein aggregation.

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 ?-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 ?-synuclein aggregation. Secretion of ?-synuclein was also elevated in the culture medium upon trehalose treatment, thereby significantly increasing intercellular transmission of this protein. Despite the substantial increase in ?-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.

SUBMITTER: Yoon YS

PROVIDER: S-EPMC5682667 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Is trehalose an autophagic inducer? Unraveling the roles of non-reducing disaccharides on autophagic flux and alpha-synuclein aggregation.

Yoon Ye-Seul YS Cho Eun-Duk ED Jung Ahn Woo W Won Lee Kyung K Lee Seung-Jae SJ Lee He-Jin HJ

Cell death & disease 20171005 10

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, treh ...[more]

PMID: 28981090

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Project description:Beta-amyloid (A?) burden and impaired neuronal autophagy contribute to secondary brain injury after traumatic brain injury (TBI). 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS) treatment has been reported to reduce A? aggregation and rescue behavioral deficits in Alzheimer's disease-like mice. Here, we investigated neuroprotective effects of EPPS in a mouse model of TBI. Mice subjected to controlled cortical impact (CCI) were treated with EPPS (120?mg/kg, orally) immediately after CCI and thereafter once daily for 3 or 7?days. We found that EPPS treatment profoundly reduced the accumulation of beta-amyloid precursor protein (?-APP) and A? over a widespread area detected in the pericontusional cortex, external capsule (EC), and hippocampal CA1 and CA3 at 3?days after TBI, accompanied by significant reduction in the TBI-induced diffuse axonal injury identified by increased immunoreactivity of SMI-32 (an indicator for axonal damage). We also found that EPPS treatment ameliorated the TBI-induced synaptic damage (as reflected by enhanced postsynaptic density 95, PSD-95), and impairment of autophagy flux in the neurons as reflected by reduced autophagy markers (LC3-II/LC3-I ratio and p62/SQSTM1) and increased lysosomal enzyme cathepsin D (CTSD) in neurons detected in the cortex and hippocampal CA1. As a result, EPPS treatment significantly reduced the TBI-induced early neuronal apoptosis (assessed by active caspase-3), and eventually prevented cortical tissue loss and hippocampal neuronal loss at 28?days after TBI. Additionally, we found that inhibition of autophagic flux with chloroquine by decreasing autophagosome-lysosome fusion significantly reversed the decreased expressions of neuronal p62/SQSTM1 and apoptosis by EPPS treatment. These data suggest that the neuroprotection by EPPS is, at least in part, related to improved autophagy flux. Finally, we found that EPPS treatment significantly improved the cortex-dependent motor and hippocampal-dependent cognitive deficits associated with TBI. Taken together, these findings support the further investigation of EPPS as a treatment for TBI.

Dataset Information

Is trehalose an autophagic inducer? Unraveling the roles of non-reducing disaccharides on autophagic flux and alpha-synuclein aggregation.

Publications

Is trehalose an autophagic inducer? Unraveling the roles of non-reducing disaccharides on autophagic flux and alpha-synuclein aggregation.

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