STEP₆₁ is a substrate of the E3 ligase parkin and is upregulated in Parkinson’s disease

Significance In neurons, STEP ₆₁ (striatal-enriched protein tyrosine phosphatase) protein levels are tightly regulated, and the protein’s up-regulation is implicated in several neuropsychiatric disorders. Here, we demonstrate that parkin is a major E3 ligase regulating STEP ₆₁ levels through the ubiquitin proteasome system. In Parkinson’s disease, in which parkin function is compromised, STEP ₆₁ levels increase, which is associated with down-regulation of synaptic proteins required for neuronal plasticity. Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). The loss of SNc dopaminergic neurons affects the plasticity of striatal neurons and leads to significant motor and cognitive disabilities during the progression of the disease. PARK2 encodes for the E3 ubiquitin ligase parkin and is implicated in genetic and sporadic PD. Mutations in PARK2 are a major contributing factor in the early onset of autosomal-recessive juvenile parkinsonism (AR-JP), although the mechanisms by which a disruption in parkin function contributes to the pathophysiology of PD remain unclear. Here we demonstrate that parkin is an E3 ligase for STEP ₆₁ (striatal-enriched protein tyrosine phosphatase), a protein tyrosine phosphatase implicated in several neuropsychiatric disorders. In cellular models, parkin ubiquitinates STEP ₆₁ and thereby regulates its level through the proteasome system, whereas clinically relevant parkin mutants fail to do so. STEP ₆₁ protein levels are elevated on acute down-regulation of parkin or in PARK2 KO rat striatum. Relevant to PD, STEP ₆₁ accumulates in the striatum of human sporadic PD and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mice. The increase in STEP ₆₁ is associated with a decrease in the phosphorylation of its substrate ERK1/2 and the downstream target of ERK1/2, pCREB [phospho-CREB (cAMP response element-binding protein)]. These results indicate that STEP ₆₁ is a novel substrate of parkin, although further studies are necessary to determine whether elevated STEP ₆₁ levels directly contribute to the pathophysiology of PD.