Lactulose and Melibiose Inhibit α-Synuclein Aggregation and Up-Regulate Autophagy to Reduce Neuronal Vulnerability.

Abstract

Parkinson's disease (PD) is a neurodegenerative disease characterized by selective dopaminergic (DAergic) neuronal degeneration in the substantia nigra (SN) and proteinaceous α-synuclein-positive Lewy bodies and Lewy neuritis. As a chemical chaperone to promote protein stability and an autophagy inducer to clear aggregate-prone proteins, a disaccharide trehalose has been reported to alleviate neurodegeneration in PD cells and mouse models. Its trehalase-indigestible analogs, lactulose and melibiose, also demonstrated potentials to reduce abnormal protein aggregation in spinocerebellar ataxia cell models. In this study, we showed the potential of lactulose and melibiose to inhibit α-synuclein aggregation using biochemical thioflavin T fluorescence, cryogenic transmission electron microscopy (cryo-TEM) and prokaryotic split Venus complementation assays. Lactulose and melibiose further reduced α-synuclein aggregation and associated oxidative stress, as well as protected cells against α-synuclein-induced neurotoxicity by up-regulating autophagy and nuclear factor, erythroid 2 like 2 (NRF2) pathway in DAergic neurons derived from SH-SY5Y cells over-expressing α-synuclein. Our findings strongly indicate the potential of lactulose and melibiose for mitigating PD neurodegeneration, offering new drug candidates for PD treatment.

• Authors: Chiung Mei Chen, Chih-Hsin Lin, Yih-Ru Wu, Chien-Yu Yen, Yu-Ting Huang, Jia-Lan Lin, Chung-Yin Lin, Wan-Ling Chen, Chih-Ying Chao, Guey-Jen Lee-Chen, Ming-Tsan Su, Kuo-Hsuan Chang
• Journal: Cells (Cells) Vol. 9 Issue 5 (05 16 2020) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 32429337 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Benzothiazoles
• Neuroprotective Agents
• Protein Aggregates
• alpha-Synuclein
• Green Fluorescent Proteins
• thioflavin T
• Lactulose
• Melibiose
• Trehalose

Topics

• Amino Acid Sequence
• Antioxidants (pharmacology)
• Autophagy (drug effects)
• Benzothiazoles (metabolism)
• Cell Line
• Cell Survival (drug effects)
• Dopaminergic Neurons (drug effects, metabolism)
• Fluorescence
• Green Fluorescent Proteins (metabolism)
• Humans
• Lactulose (chemistry, pharmacology)
• Melibiose (chemistry, pharmacology)
• Neuronal Outgrowth (drug effects)
• Neurons (drug effects, metabolism)
• Neuroprotective Agents (pharmacology)
• Oxidative Stress (drug effects)
• Protein Aggregates (drug effects)
• Trehalose (chemistry, pharmacology)
• Up-Regulation (drug effects)
• alpha-Synuclein (chemistry, metabolism)