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

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

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)120-130
Number of pages11
JournalNeuroToxicology
Volume48
DOIs
Publication statusPublished - May 1 2015
Externally publishedYes

Keywords

  • Autophagy
  • Lactulose
  • Melibiose
  • Neurodegenerative disease
  • Trehalase

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

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