Isorhynchophylline, a natural alkaloid, promotes the degradation of alpha-synuclein in neuronal cells via inducing autophagy.

Abstract

Accumulation of α-synuclein (α-syn) in the brain is a pathogenic feature and also a causative factor of Parkinson disease. Isorhynchophylline (IsoRhy) is a major tetracyclic oxindole alkaloid isolated from the Chinese herbal medicine Uncaria rhynchophylla (Miq.)Jacks (Gouteng in Chinese), which has been used for the treatment of neurological diseases in East Asia for centuries. Here we report a novel function of IsoRhy as a neuronal autophagy inducer. IsoRhy induced autophagy in different neuronal cell lines, including N2a, SH-SY5Y and PC12 cells, and also in primary cortical neurons. Furthermore, IsoRhy induced autophagy in the fat bodies of Drosophila. IsoRhy promoted clearance of wild-type, A53T and A30P α-syn monomers, α-syn oligomers and α-syn/synphilin-1 aggresomes in neuronal cells via the autophagy-lysosome pathway. More importantly, IsoRhy was able to decrease the expression levels of wild-type and A53T α-syn protein in differentiated human dopaminergic neurons. Notably, IsoRhy-induced autophagy was independent of the mTOR pathway but dependent on the function of Beclin 1. Taken together, data from this study raise the possibility that oxindole alkaloid derivatives may serve as a means to stimulate autophagy in neuronal cells, thereby exerting preventive and therapeutic values against neurodegenerative diseases such as Parkinson disease by reducing pathogenic protein aggregates in neurons.

• Authors: Jia-Hong Lu, Jie-Qiong Tan, Siva Sundara Kumar Durairajan, Liang-Feng Liu, Zhuo-Hua Zhang, Long Ma, Han-Ming Shen, H Y Edwin Chan, Min Li
• Journal: Autophagy (Autophagy) Vol. 8 Issue 1 Pg. 98-108 (Jan 2012) ISSN: 1554-8635 [Electronic] United States
• PMID: 22113202 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Indole Alkaloids
• Membrane Proteins
• Oxindoles
• alpha-Synuclein
• rhyncophylline
• TOR Serine-Threonine Kinases

Topics

• Animals
• Autophagy (drug effects)
• Biomarkers (metabolism)
• Cell Differentiation (drug effects)
• Cell Line
• Dopaminergic Neurons (cytology, drug effects, metabolism)
• Drosophila melanogaster (cytology)
• Embryonic Stem Cells (cytology, drug effects, metabolism)
• Fat Body (cytology, drug effects, metabolism)
• Humans
• Indole Alkaloids (chemistry, pharmacology)
• Larva (cytology, drug effects, metabolism)
• Membrane Proteins (metabolism)
• Mice
• Neurons (cytology, drug effects, metabolism)
• Oxindoles
• Proteolysis (drug effects)
• Rats
• TOR Serine-Threonine Kinases (metabolism)
• alpha-Synuclein (metabolism)