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Funded Studies

Identification of the Parkin-binding Domain for SLP-2 as a Potential Therapeutic Target

Objective/Rationale:
Defects in mitochondria (the “powerhouse” of the cell) are implicated in Parkinson’s disease (PD), and the protein parkin is known to be involved in controlling mitochondrial health. An important step for better understanding how parkin does this is to get a more comprehensive understanding of which proteins interact with parkin and how they support its protective function on mitochondria. We will investigate the role of a newly identified interaction between a mitochondrial protein and parkin and the effects of this on mitochondrial health. 

Project Description:
We will first identify the parkin domain most important for its interaction with a mitochondrial protein. Based on the crystal structure of the parkin protein, we will identify candidate binding sites using bioinformatic methods. We will then investigate, using patient fibroblasts and induced pluripotent stem cell (iPSC)-derived neurons, whether PD-linked parkin gene mutations lead to an abolished or weakened binding between the parkin protein and this protein, and whether this will compromise mitochondrial function. 

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Our hypothesis is that the normal interaction between parkin and this mitochondrial protein is important for mitochondrial health, and therefore parkin gene mutations might disrupt this interaction. By identifying the interaction domains on parkin, we will enable further studies to test ways to mimic this protein-protein interaction. 

Anticipated Outcome:
The successful mapping of the parkin domain responsible for the interaction will permit us to explore the use of parkin fragments or other biological tools to restore the effect of an abolished or weakened binding of parkin to this mitochondrial protein, and in doing so be able to replace the interaction we believe important to keep mitochondria healthy. This might represent a novel and differentiating therapeutic approach, specifically targeting the mitochondrial dysfunction implicated in the disease mechanisms of parkin-related PD.

Final Outcome

Mitochondria, the essential "powerhouses" of the cell, have been found to be compromised in Parkinson's disease. The protein parkin is involved in processes that help keep the mitochondria healthy through interaction with other proteins. The objective of our project was to investigate the part of parkin that interacts with Stomatin-like protein 2 (SLP-2), which is a mitochondrial protein we recently identified as being able to interact with parkin. We believe this interaction is important for maintaining healthy mitochondria, and thus set out to examine the effects of this interaction on mitochondrial function in different cell types including induced pluripotent stem cell (iPSC)-derived neurons of parkin mutation carriers.

We have successfully confirmed the interaction between these two proteins in skin fibroblasts and iPSC-derived neurons and have identified the regions of the parkin protein most important for the interaction with SLP-2. Furthermore, we have observed that this binding is weakened in patient fibroblasts harboring different types of parkin mutations, which we believe ultimately leads to a compromised mitochondrial function as measured in iPSC-derived neurons of patients.

Further studies could test the possibility to rescue this interrupted binding between parkin and SLP-2 in parkin mutation carriers and see whether this helps restore mitochondrial health. We believe our findings so far have opened up new avenues for better understanding how parkin regulates mitochondrial health under physiological conditions in neurons, and these results could form the basis of a novel therapeutic approach based on parkin peptidomimetics.

April 2015


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