3-Anhydro-6-hydroxy-ophiobolin A, a fungal sesterterpene from Bipolaris oryzae induced autophagy and promoted the degradation of α-synuclein in PC12 cells

Abstract

Autophagy is defined as an evolutionarily conserved process responsible for degradation of the cytoplasmic components including protein aggregates via the lysosomal machinery. Increasing evidence has linked defective autophagic degradation of protein aggregates with the pathogenesis of neurodegenerative disorders, and it is suggested that promotion of autophagy is regarded as a potential therapeutic for these diseases including Parkinson's disease (PD). Here we identified, 3-anhydro-6-hydroxy-ophiobolin A (X15-2), an ophiobolin derivative from Bipolaris oryzae that can strongly induce autophagic degradation of α-synuclein, the major constituent of Lewy bodies. We showed that X15-2 induced autophagy is dependent on both Beclin1 and Beclin2. Knockout of ATG5 by CRISPER/Cas9 prevented X15-2 induced autophagy and degradation of α-synuclein. Mechanistically, we showed that X15-2 induces ROS and the activation of JNK signaling for the autophagic degradation of α-synuclein in PC12 cells.

Keywords: 3-Anhydro-6-hydroxy-ophiobolin A; Autophagy; ROS; α-Synuclein.