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

Jia Hong Lu, Jie Qiong Tan, S S Kumar DURAIRAJAN, Liangfeng LIU, Zhuo Hua Zhang, Long Ma, Han Ming Shen, Ho Yin Edwin Chan, Min LI*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

108 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)98-108
Number of pages11
JournalAutophagy
Volume8
Issue number1
DOIs
Publication statusPublished - 1 Jan 2012

Scopus Subject Areas

  • Molecular Biology
  • Cell Biology

User-Defined Keywords

  • Alpha-synuclein
  • Autophagy
  • Isorhynchophylline
  • Neuron
  • Oligomers
  • Parkinson disease
  • Protein aggregates

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