The potential of lactulose and melibiose, two novel trehalase-indigestible and autophagy-inducing disaccharides, for polyQ-mediated neurodegenerative disease treatment.

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.

• Authors: Guan-Chiun Lee, Chih-Hsin Lin, Yu-Chen Tao, Jinn-Moon Yang, Kai-Cheng Hsu, Yin-Jung Huang, Shih-Han Huang, Pin-Jui Kung, Wan-Ling Chen, Chien-Ming Wang, Yih-Ru Wu, Chiung-Mei Chen, Jung-Yaw Lin, Hsiu Mei Hsieh-Li, Guey-Jen Lee-Chen
• Journal: Neurotoxicology (Neurotoxicology) Vol. 48 Pg. 120-30 (May 2015) ISSN: 1872-9711 [Electronic] Netherlands
• PMID: 25800379 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Neuroprotective Agents
• Peptides
• Protein Aggregates
• TATA-Box Binding Protein
• TBP protein, human
• polyglutamine
• Lactulose
• Melibiose
• Trehalose
• Trehalase

Topics

• Animals
• Autophagy (drug effects)
• Cell Line
• Computer-Aided Design
• Digestion
• Disease Models, Animal
• Drug Design
• Drug Stability
• Hydrogen Bonding
• Hydrolysis
• Lactulose (chemistry, metabolism, pharmacology)
• Melibiose (chemistry, metabolism, pharmacology)
• Mice, Transgenic
• Molecular Docking Simulation
• Molecular Structure
• Neurodegenerative Diseases (genetics, metabolism, pathology, prevention & control)
• Neuroprotective Agents (chemistry, metabolism, pharmacology)
• Peptides (genetics, metabolism)
• Protein Aggregates
• Purkinje Cells (drug effects, metabolism, pathology)
• Structure-Activity Relationship
• TATA-Box Binding Protein (genetics, metabolism)
• Time Factors
• Transfection
• Trehalase (metabolism)
• Trehalose (chemistry, metabolism, pharmacology)