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Funded Studies

Role of Striatal-Enriched Protein Tyrosine Phosphatase 61 (STEP61) in Parkinson's Disease

The Park2 gene product parkin is implicated in both genetic and sporadic forms of Parkinson’s disease (PD). Defective parkin function leads to the accumulation of toxic proteins, which are responsible for the pathophysiological deficits observed in PD. Our objective is to determine whether STriatal-Enriched protein tyrosine Phosphatase (STEP61) is a substrate for parkin. We will test whether deficits in parkin function (due to genetic or environmental causes) leads to the inappropriate degradation and accumulation of STEP, which in turn contributes to the pathophysiology of PD.

Project Description:
We will use in vitro cultured dopaminergic cell lines (SH- SY5Y), as well as a parkin preclinical models to validate that STEP is a substrate for parkin. Our biochemical experiments will determine whether ( i) parkin ubiquitinates STEP, which normally would lead to the degradation of STEP by proteasome; (ii) the loss of parkin function (after genetic or environmental insults, such as 6-hydroxy dopamine or rotenone treatments) leads to an inappropriate accumulation of STEP. The accumulated STEP will modify critical proteins that oppose synaptic strengthening and neuronal survival mechanisms, thereby initiating cell death pathways.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
STEP levels and activity are elevated in several CNS disorders, including Alzheimer’s disease. This project will establish whether STEP is also implicated in Parkinson’s disease, which will help to validate STEP as a target for drug discovery. Our long-term goals are to discover STEP inhibitors that have the potential for being novel therapeutic agents for the treatment of Parkinson’s disease.

Anticipated Outcome:
This study will provide valuable information on the regulation of STEP and its downstream pathways, and how these pathways are involved in the etiology of Parkinson’s disease. It will also help establish proof of concept evidence for discovering STEP inhibitors for the treatment of Parkinson’s disease.


Progress Report


Parkin is an E3 ligase encoded by Park2 gene. Dysfunction of parkin is implicated in both genetic and sporadic cases of Parkinson ’s disease (PD). Identification of new substrates of parkin and studying its physiological role is important to understand the etiology of PD. Our studies show Striatal Enriched Tyrosine Phosphatase (STEP) is a substrate for parkin. Parkin regulates the normal turnover of STEP in brain cells. Genetic loss of parkin in pre-clinical models or mutations in the park2 gene in Human PD patient’s brain affects normal STEP turnover and leads to accumulation of STEP. In relevance to Sporadic PD, exposure of environmental toxin such as rotenone affects STEP turnover in dopaminergic neuronal cells. This study validates STEP is implicated in both genetic and sporadic forms of PD and expands a new area of research on regulation of STEP in the progression of PD.

Presentations & Publications

Abstract submitted for Society for Neuroscience conference, which  will be held on Oct 13-17, 2012 at New Orleans.

Title: Role of Striatal-Enriched protein tyrosine Phosphatase (STEP) in Parkinson’s Disease (PD).

Pradeep Kurup1*, Jian Xu1, Chimezie Ononenyi1, Angus C. Nairn2 and Paul J. Lombroso1

1Child Study Center and 2Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, 06520

May 2012




  • Pradeep Kotapurathu Kurup, PhD

    New Haven, CT United States

  • Paul J. Lombroso, MD

    New Haven, CT United States

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