Parkinson disease-associated protein DJ-1 regulates the autophagic-lysosomal pathway through ROS-dependent modulation of the AMPK/mTORC1 axis

ABSTRACT Mutations in the protein DJ-1 are linked to familial forms of Parkinson’s disease (PD). The protein has been well-documented to exert a role in energy metabolism and antioxidant defense, contributing to the maintenance of mitochondrial homeostasis. We and others have previously observed that DJ-1 can also influence autophagy, but the mechanisms are still incompletely defined. In this study, using complementary cellular and animal models, we characterize the impact of DJ-1 loss on the autophagic pathway. Our data demonstrate that DJ-1 deficiency impairs autophagosome-lysosome fusion and lysosomal degradation, resulting in the accumulation of dysfunctional autolysosomes and the subsequent buildup of autophagic substrates. Mechanistically, we show that elevated reactive oxygen species (ROS) in DJ-1-null models inhibit the energy-sensing AMP-activated protein kinase (AMPK), thereby activating the autophagy suppressor mechanistic target of rapamycin 1 (mTORC1). Collectively, these findings delineate a novel signaling axis linking oxidative stress to autophagic dysfunction, providing new insights into the cellular mechanisms underlying autophagic dysfunction in PD. Competing Interest Statement The authors have declared no competing interest. Abbreviation list - ALP - autophagic-lysosomal pathway - AMPK - AMP-activated protein kinase - AMPK-CA - constitutive active form of AMP-activated protein kinase - pAMPK - phosphorylated form of AMP-activated protein kinase - DHE - dihydroethidium - GBA1 - glucocerebrosidase 1 gene - GCase - glucocerebrosidase 1 protein - KO - knockout - iPSCs - induced pluripotent stem cells - LC3 - microtubule-associated protein 1A/1B-light chain - mTORC1 - mechanistic target of rapamycin complex 1 - NAC - N-acetylcysteine - PD - Parkinson disease - p-S6K - phosphorylated form of ribosomal protein S6 kinase beta-1 - ROS - reactive oxygen species - S6K - ribosomal protein S6 kinase beta-1 - TH - tyrosine hydroxylase - WB - western blot - WT - wild-type