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

Abstract

Accumulation of a-synuclein (a-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 a-syn monomers, a-syn oligomers and a-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 a-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.

HMGB1 is involved in autophagy inhibition caused by SNCA/α-synuclein overexpression

“…In iPC12 cells, the decrease in LC3-II and BECN1 levels was reversed by treatment with corynoxine B (Cory B, a natural autophagy inducer previously discovered by us 16 ) and rapamycin (Rap, an MTOR-dependent autophagy inducer) (Fig. 6A-C).…”

“…Pharmacological induction of autophagy by a range of small molecules promotes the clearance of aggregateprone proteins including SNCA species. [14][15][16] SNCA forms a reciprocal relationship with protein degradation pathways. 17 Both UPS and ALP activity decline with aging, which may result in SNCA accumulation due to impaired clearance.…”

Induction of reactive oxygen species-stimulated distinctive autophagy by chelerythrine in non-small cell lung cancer cells

“…For quantitative assay, the red-puncta and green-puncta numbers were counted as described previously [33], [34]. Briefly, at least 20 cells (per experiment) were randomly selected for counting the number of mRFP-LC3 or EGFR-LC3 puncta in each group, and three independent experiments were performed.…”

The comparison of three methods of drawing cerebrospinal fluid in rabbit

“…CSF analysis is vital to the diagnosis of many diseases (Borawake et al, 2011;Wang et al, 2012;Wauters et al, 2012;Palm et al, 2008) because some disease related specific substance, such as antibody, specific protein or pathogen can only be found through analyzing CSF. Recently, the actions of natural medicine on some central nervous system degenerative diseases, such as Parkinson's disease and Alzheimer's disease, have been reported by clinical and experimental researches (Lu et al, 2012;Mancuso et al, 2012;Tseng et al, 2011;Mandel et al, 2012;Capiralla et al, 2012), the analysis of CSF in these researches is believed to be a reliable way for searching the effective components of the natural medicine on this system (Yang et al, 2011). Drawing CSF is the first step for the analysis and there are many ways.…”