title: 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: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors: Guan-Chiun
authors: GC
authors: Lee
authors: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.
authors: Chih-Hsin
authors: CH
authors: Lin
authors: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors: Yu-Chen
authors: YC
authors: Tao
authors: Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.
authors: Jinn-Moon
authors: JM
authors: Yang
authors: Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.
authors: Kai-Cheng
authors: KC
authors: Hsu
authors: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors: Yin-Jung
authors: YJ
authors: Huang
authors: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors: Shih-Han
authors: SH
authors: Huang
authors: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors: Pin-Jui
authors: PJ
authors: Kung
authors: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.
authors: Wan-Ling
authors: WL
authors: Chen
authors: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors: Chien-Ming
authors: CM
authors: Wang
authors: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.
authors: Yih-Ru
authors: YR
authors: Wu
authors: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.
authors: Chiung-Mei
authors: CM
authors: Chen
authors: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors: Jung-Yaw
authors: JY
authors: Lin
authors: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan. Electronic address: hmhsieh@ntnu.edu.tw.
authors: Hsiu Mei
authors: HM
authors: Hsieh-Li
authors: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan. Electronic address: t43019@ntnu.edu.tw.
authors: Guey-Jen
authors: GJ
authors: Lee-Chen
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D017076:Computer-Aided Design; D004063:Digestion; D004195:Disease Models, Animal; D015195:Drug Design; D004355:Drug Stability; D006860:Hydrogen Bonding; D006868:Hydrolysis; D007792:Lactulose / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008553:Melibiose / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008822:Mice, Transgenic; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D066329:Protein Aggregates; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013329:Structure-Activity Relationship; D035181:TATA-Box Binding Protein / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014198:Trehalase / Q000378:metabolism*; D014199:Trehalose / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018696:Neuroprotective Agents; D010455:Peptides; D066329:Protein Aggregates; D035181:TATA-Box Binding Protein; C509817:TBP protein, human; C097188:polyglutamine; D007792:Lactulose; D008553:Melibiose; D014199:Trehalose; D014198:Trehalase
keywords: Autophagy; Lactulose; Melibiose; Neurodegenerative disease; Trehalase