Onjisaponin B Derived from Radix Polygalae Enhances Autophagy and Accelerates the Degradation of Mutant α-Synuclein and Huntingtin in PC-12 Cells

Abstract

Emerging evidence indicates important protective roles being played by autophagy in neurodegenerative disorders through clearance of aggregate-prone or mutant proteins. In the current study, we aimed to identify autophagy inducers from Chinese medicinal herbs as a potential neuroprotective agent that enhances the clearance of mutant huntingtin and α-synuclein in PC-12 cells. Through intensive screening using the green fluorescent protein-light chain 3 (GFP-LC3) autophagy detection platform, we found that the ethanol extracts of Radix Polygalae (Yuan Zhi) were capable of inducing autophagy. Further investigation showed that among three single components derived from Radix Polygalae—i.e., polygalacic acid, senegenin and onjisaponin B—onjisaponin B was able to induce autophagy and accelerate both the removal of mutant huntingtin and A53T α-synuclein, which are highly associated with Huntington disease and Parkinson disease, respectively. Our study further demonstrated that onjisaponin B induces autophagy via the AMPK-mTOR signaling pathway. Therefore, findings in the current study provide detailed insights into the protective mechanism of a novel autophagy inducer, which is valuable for further investigation as a new candidate agent for modulating neurodegenerative disorders through the reduction of toxicity and clearance of mutant proteins in the cellular level.

Recent advances in autophagy-based neuroprotection

“…Chen et al [117] showed that rapamycin significantly reduced the accumulation of mutant Htt-552, and increased glutamate transporter 1 expression and [(3)H] glutamate uptake in astrocytes infected with adenovirus carrying codon gene of N-terminal 552 residues of huntingtin. Wu et al [118] showed that onjisaponin of the Radix Polygalae (Yuan Zhi) accelerated the removal of mutant huntingtin in PC12 cells by inducing autophagy via the AMPK-mTOR signaling pathway. Rose et al [119] reported that rilmenidine, a well-tolerated antihypertensive drug, attenuated signs and reduced levels of huntingtin fragments through mTORindependent autophagic pathway disease in a mouse model of HD.…”

“…Degradation of Ab and a-synuclein AD and PD [58] Rilmenidine A well-tolerated antihypertensive drug Reduction of huntingtin level through mTOR-independent autophagic pathway HD [119] Curcumin A principal component of the spice turmeric Inhibition of mTOR pathway AD and PD [23,63,103] Onjisaponin Active principle of Radix Polygalae (Yuan Zhi) AMPK-mTOR signaling pathway HD [118] Ab: b-Amyloid; AD: Alzheimer's disease; AMPK: AMP-activated protein kinase; HD: Huntington's disease; PD: Parkinson's disease.…”

Natural Compounds as Therapeutic Agents for Amyloidogenic Diseases

“…Onjisaponin B was able to induce autophagy and accelerate both the removal of mutant huntingtin and A53T '-synuclein, associated with Huntington's and Parkinson's diseases (Ling et al 2013;Wu et al 2013a) Radix Glycyrrhizae (RG) and the active constituent isoliquiritigenin RG antioxidant activity related to flavonoids and total phenolics . …”

Brain Food for Alzheimer-Free Ageing: Focus on Herbal Medicines

“…Onjisaponin B was able to induce autophagy and accelerate both the removal of mutant huntingtin and A53T '-synuclein, associated with Huntington's and Parkinson's diseases (Ling et al 2013;Wu et al 2013a) Radix Glycyrrhizae (RG) and the active constituent isoliquiritigenin RG antioxidant activity related to flavonoids and total phenolics . Prevented A"(25-35)-induced neuronal apoptotic death by interfering with the increases of intracellular Ca 2C and ROS, and RG potential therapeutic for preventing the progression of AD (Lee et al 2012) …”