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

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.