GSK-3 mediates nuclear translocation of p62/SQSTM1 in MPTP-induced mouse model of Parkinson’s disease

Abstract

p62/SQSTM1 is a multifunctional, cytoplasmic protein with fundamental roles in autophagy and antioxidant responses. Here we showed that p62 translocated from the cytoplasm to the nucleus in nigral dopaminergic neurons in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrid (MPTP)-induced mouse model of Parkinson s disease (PD). We found that p62 was physically associated with glycogen synthase kinase (GSK)-3β, a serine/threonine protein kinase implicated in dopaminergic neurodegeneration in PD, and that MPTP treatment promoted dissociation of the complex in mice. Conditional knockout of GSK-3 prevented nuclear translocation of p62, suggesting that this translocation was detrimental to dopaminergic neurons. p62 knockout mice were used to investigate the role of p62 in MPTP-induced neuronal death. Knockout of p62 aggravated neuronal injury induced by MPTP intoxication, suggesting that p62 plays an important role in dopaminergic cell survival in stress conditions. Together, our data demonstrate that GSK-3 mediates nuclear translocation of p62 during MPTP-induced parkinsonian neurodegeneration. These findings shed new light on the role of the cytoplasmic-nuclear shuttling of p62 and the mechanism underlying GSK-3-depedent neuronal death in PD pathogenesis.