Functions Of PICK1in Oxidative Stress And Its Molecular Mechanism

Protein interacting with C-kinase1(PICK1) has received considerable attention, as it interacts with a broad range of neurotransmitter receptors, transporters and enzymes, and thereby influences their localization and functions in the central nervous system. It has been suggested that disrupted interactions between PICK1and putative partners are involved in neurological diseases such as schizophrenia, Parkinson’s disease, chronic pain, and amyotrophic lateral sclerosis. However, the functions of PICK1in neurological disorders are not clear. Here, we showed increased oxidative stress in PICK1-/-mice as well as in a patient with homozygous PICK1-mutantion. The oxidation in PICK1-/-mice occurred selectively in neurons and was age-dependent, leading to microglial activation and the release of inflammatory factors with aging. Neurons in the cortex and hippocampus from PICK1-/-mice showed increased vulnerability to oxidants and reduced capacity to metabolize reactive oxygen species; this was caused by reduced glutathione content and impaired cysteine transport. The dysregulated expression of glutathione was attributed to a decrease of the surface glutamate transporter EAAC1. Overexpression of PICK1could rescue the surface expression of EAAC1and ameliorate the glutathione deficit in PICKl neurons. Finally, reduced surface EAAC1was associated with defective Rabll activity. Taken together, these results indicate that PICKl is a crucial regulator in glutathione homeostasis and plays important roles in oxidative stress and its associated neurodegenerative diseases.