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The potential of lactulose and melibiose, two novel trehalase-indigestible and autophagy-inducing disaccharides, for polyQ-mediated neurodegenerative disease treatment.
- Source :
-
Neurotoxicology [Neurotoxicology] 2015 May; Vol. 48, pp. 120-30. Date of Electronic Publication: 2015 Mar 20. - Publication Year :
- 2015
-
Abstract
- The unique property of trehalose encourages its pharmaceutical application in aggregation-mediated neurodegenerative disorders, including Alzheimer's, Parkinson's, and many polyglutamine (polyQ)-mediated diseases. However, trehalose is digested into glucose by trehalase and which reduced its efficacy in the disease target tissues. Therefore, searching trehalase-indigestible analogs of trehalose is a potential strategy to enhance therapeutic effect. In this study, two trehalase-indigestible trehalose analogs, lactulose and melibiose, were selected through compound topology and functional group analyses. Hydrogen-bonding network analyses suggest that the elimination of the hydrogen bond between the linker ether and aspartate 321 (D321) of human trehalase is the key for lactulose and melibiose to avoid the hydrolyzation. Using polyQ-mediated spinocerebellar ataxia type 17 (SCA17) cell and slice cultures, we found the aggregation was significantly prohibited by trehalose, lactulose, and melibiose, which may through up-regulating of autophagy. These findings suggest the therapeutic applications of trehalase-indigestible trehalose analogs in aggregation-associated neurodegenerative diseases.<br /> (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Cell Line
Computer-Aided Design
Disease Models, Animal
Drug Stability
Hydrogen Bonding
Hydrolysis
Lactulose chemistry
Lactulose metabolism
Melibiose chemistry
Melibiose metabolism
Mice, Transgenic
Molecular Docking Simulation
Molecular Structure
Neurodegenerative Diseases genetics
Neurodegenerative Diseases metabolism
Neurodegenerative Diseases pathology
Neuroprotective Agents chemistry
Neuroprotective Agents metabolism
Peptides genetics
Protein Aggregates
Purkinje Cells drug effects
Purkinje Cells metabolism
Purkinje Cells pathology
Structure-Activity Relationship
TATA-Box Binding Protein genetics
TATA-Box Binding Protein metabolism
Time Factors
Transfection
Trehalose chemistry
Trehalose metabolism
Trehalose pharmacology
Autophagy drug effects
Digestion
Drug Design
Lactulose pharmacology
Melibiose pharmacology
Neurodegenerative Diseases prevention & control
Neuroprotective Agents pharmacology
Peptides metabolism
Trehalase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1872-9711
- Volume :
- 48
- Database :
- MEDLINE
- Journal :
- Neurotoxicology
- Publication Type :
- Academic Journal
- Accession number :
- 25800379
- Full Text :
- https://doi.org/10.1016/j.neuro.2015.03.009