STEP ₆₁ is a substrate of the E3 ligase parkin and is upregulated in Parkinson’s disease

Abstract

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 STEP61 (striatal-enriched protein tyrosine phosphatase), a protein tyrosine phosphatase implicated in several neuropsychiatric disorders. In cellular models, parkin ubiquitinates STEP61 and thereby regulates its level through the proteasome system, whereas clinically relevant parkin mutants fail to do so. STEP61 protein levels are elevated on acute down-regulation of parkin or in PARK2 KO rat striatum. Relevant to PD, STEP61 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 STEP61 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 STEP61 is a novel substrate of parkin, although further studies are necessary to determine whether elevated STEP61 levels directly contribute to the pathophysiology of PD.

Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models

“…Increased STEP 61 levels seem to derive from disruptions in the ubiquitination and degradation of STEP 61 , which are regulated, at least in part, by NRG1 signaling. This is consistent with evidence that genes involved in UPS are down-regulated in postmortem SZ cortical tissue 55, 56 , and similar to what is observed in neurodegenerative diseases 5, 7, 57 . While further work will clarify whether other mechanisms also affect STEP 61 protein levels, our findings suggest that inhibition of STEP 61 activity might prove to be a promising point of therapeutic intervention for the subset of SZ patients in which STEP 61 levels are increased.…”

Inhibition of the tyrosine phosphatase STEP61 restores BDNF expression and reverses motor and cognitive deficits in phencyclidine-treated mice

“…Recent studies have shown that disruptions of the UPS contribute to the accumulation of STEP 61 in MK-801-treated neuronal cultures and mice [2] and Parkinson’s disease patients [53]. Here we demonstrate that disruption of STEP 61 ubiquitination also may contribute to its accumulation in PCP-treated cultures and in mice.…”

“…Both high [2, 32, 51–53] and low [54–56] levels of STEP activity are implicated in a growing number of neuropsychiatric and neurodegenerative disorders. Dysfunctional BDNF/TrkB signaling is implicated in many of the same neurodegenerative and neuropsychiatric disorders [9], but in an opposite direction.…”

BDNF Induces Striatal-Enriched Protein Tyrosine Phosphatase 61 Degradation Through the Proteasome

“…Thus, the present results improve our understanding of the mechanisms underlying BDNF regulation of neuronal function and suggest that STEP 61 degradation could play an important role in this process. In agreement, STEP levels/activity are altered in neurodegenerative diseases in which cortical, striatal, and/or hippocampal function is impaired, including Alzheimer’s disease, Huntington’s chorea, Parkinson’s disease, schizophrenia, and fragile X syndrome [18, 32–35, 62]. Since BDNF also regulates survival, maturation, and differentiation of these neurons [63–68], future studies are needed to address the contribution of BDNF-induced STEP 61 degradation to these phenomena.…”