Mechanism of neuroprotection by trehalose: controversy surrounding autophagy induction

He-Jin Lee, Ye-Seul Yoon, Seung-Jae Lee, He-Jin Lee, Ye-Seul Yoon, Seung-Jae Lee

Abstract

Trehalose is a non-reducing disaccharide with two glucose molecules linked through an α, α-1,1-glucosidic bond. Trehalose has received attention for the past few decades for its role in neuroprotection especially in animal models of various neurodegenerative diseases, such as Parkinson and Huntington diseases. The mechanism underlying the neuroprotective effects of trehalose remains elusive. The prevailing hypothesis is that trehalose protects neurons by inducing autophagy, thereby clearing protein aggregates. Some of the animal studies showed activation of autophagy and reduced protein aggregates after trehalose administration in neurodegenerative disease models, seemingly supporting the autophagy induction hypothesis. However, results from cell studies have been less certain; although many studies claim that trehalose induces autophagy and reduces protein aggregates, the studies have their weaknesses, failing to provide sufficient evidence for the autophagy induction theory. Furthermore, a recent study with a thorough examination of autophagy flux showed that trehalose interfered with the flux from autophagosome to autolysosome, raising controversy on the direct effects of trehalose on autophagy. This review summarizes the fundamental properties of trehalose and the studies on its effects on neurodegenerative diseases. We also discuss the controversy related to the autophagy induction theory and seek to explain how trehalose works in neuroprotection.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1. Trehalose metabolism.
Fig. 1. Trehalose metabolism.
a Structure of trehalose. Trehalose consists of two glucose units linked through α, α-1,1-glucosidic bond. It is a stable non-reducing sugar, which is readily hydrolyzed by the enzyme trehalase. b Trehalose synthetic pathways. Five pathways to synthesize trehalose are shown. A most common pathway is the (1)‘‘TPS/TPP’’ pathway to form trehalose-6-phosphate, which is dephosphorylated to become trehalose. (2) Trehalose synthase (TS) synthesize trehalose from maltose. (3) Maltooligosaccharides are broken down to from trehalose by the TreY/TreZ pathway. (4) Trehalose phosphorylase (TreP) utilizes glucose-1-phosphate to form trehalose. (5) ADP-glucose is used to from trehalose by trehalose glycosyltransferring synthase (TreT).
Fig. 2. Autophagic pathways.
Fig. 2. Autophagic pathways.
Activation of autophagy inhibits mTORC1 complex that leads to autophagosome formation. Atg5–atg12–atg16 complex helps elongation of phagophore membrane. Cytosolic LC3-I is converted to lipidated LC3-II and binds to inner and outer membranes of autophagosomes. Mature autophagosomes are formed and are ready for fusion with lysosomes. Lysosomal hydrolases degrade autophagosome contents.
Fig. 3. Regulation of autophagy.
Fig. 3. Regulation of autophagy.
a Distinguishing between autophagosomes and autolysosomes. mRFP-GFP tandem fluorescent-tagged LC3 (tfLC3) fluoresces both GFP and RFP signals (yellow) before it is delivered to lysosomes. GFP in tfLC3 loses its fluorescence in the acidic and degradative lysosomal environment (red). Autophagy induction increases autophagosomes (yellow) and autolysosomes (red) together because the autophagic flux to lysosomes is not disturbed. Blocking fusion of autophagosomes and lysosomes, however, would increase the number of autophagosomes (yellow) only. b Autophagy modulating factors. Autophagy is initiated through inhibition of mTORC1 complex and activation of Class III PI3K complex. 3-methyladenine (3-MA) and Wortmannin prevent autophagy through inhibition of mTORC1 complex. Trehalose may activate autophagy through PI3K. BafA1 and trehalose could both inhibit fusions of autophagosomes and lysosomes, thus blocking final stage of autophagy
Fig. 4. A schematic view of a…
Fig. 4. A schematic view of a hypothesis of trehalose function in the brain.
(1) Trehalose indirectly affects brain function through the regulation of gut microbes, which sends signals to the brain by dendritic immune activation or secretion of neurotransmitters and gut peptides that may be delivered through vagus nerve to the brain. (2) Direct transport of trehalose to the brain, which passes through the blood–brain barrier and affects neuronal cells. (3) The brain sends signals to the enteric system to modulate trehalose function

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