Beclin1 and HMGB1 ameliorate the α-synuclein-mediated autophagy inhibition in PC12 cells

Background: Aberrant alpha-synuclein aggregation due to the deficiency of ubiquitin-proteasome or of autophagy characterizes the parkinson disease (PD). High mobility group box 1 (HMGB1) is a novel stress sensor to mediate the persistent neuro-inflammation and the consequent progressive neurodegeneration, via controlling the cellular autophagy/apoptosis checkpoint during inflammation. Moreover, HMGB1 has been recently indicated to involve in the autophagic degradation of alpha-synuclein. Methods: In the current study, we investigated the influence of the overexpressed alpha-synuclein of wild type (wt) or mutant type (A53T and A30P, mt) on the cytosolic levels of HMGB1 and Beclin1 and on the starvation-induced autophagy in pheochromocytoma PC12 cells. And then we explored the overexpression of HMGB1 or of Beclin1 on the alpha-synuclein degradation and on the autophagy in the alpha-synuclein-overexpressed PC12 cells. Results: It was demonstrated that alpha-synuclein overexpression inhibited the trans-location of HMGB1 from nucleus to cytosol and reduced the cytosolic level of Beclin1 in PC12 cells, and inhibited the starvation-induced autophagy via downregulating autophagy-associated markers and via reducing the autophagic vesicles in PC12 cells under starvation. On the other side, the intracellular promotion of either HMGB1 or Beclin1 upregulated the alpha-synuclein degradation and ameliorated the alpha-synuclein-mediated autophagy reduction in PC12 cells. However, the exogenous HMGB1 treatment exerted no such regulation in PC12 cells. Conclusion: In summary, our study confirmed the positive regulation by HMGB1 and Beclin1 on the alpha-synuclein degradation and on the starvation-induced autophagy in PC12 cells, implying both markers as prominent targets to promote the alpha-synuclein degradation.