Potential of Cell-permeable Parkin Proteins as a Treatment for Parkinsonís Disease
Rapid Response Innovation Awards, 2014
Parkin is an enzyme that protects cells, including neurons, from damage. Mutations in parkin can lead to loss of neurons and contribute to Parkinsonís disease (PD). We plan to synthesize cell-permeable forms of parkin, then test whether they offer protection in cellular models of PD. If these synthetic proteins provide cellular protection, they may form the basis for novel therapeutic strategies to treat PD.†
The first part of the project will entail the synthesis of cell-permeable forms of the parkin protein. These proteins will contain a short extension, known as a cell-penetrating peptide, added to the normal parkin protein. This cell-penetrating peptide has been shown in previous studies to allow the internalization of functional proteins into cells. In the second part of the project, we will verify the enzymatic activity of the synthetic parkin proteins, and then test whether they can protect cells from damage. We will examine mitochondria, the cellsí energy-producing structures, as protection of mitochondria contributes to overall protection against developing PD.†
Relevance to Diagnosis/Treatment of Parkinsonís Disease:
To date, there are no effective therapies addressing neuronal damage and loss due to mutated parkin or parkin deficiency, which ultimately lead to PD. If we demonstrate that cell-permeable parkin proteins can protect cells from damage in PD models, these proteins may form the basis for developing novel protein replacement therapies for treating PD.†
Upon successful completion of the project, we will have evidence that may support our concept that cell-permeable parkin proteins can confer protection in cellular PD models. Future research based on these results would involve expanding the forms of cell-permeable parkins to be tested, as well as the types of cellular damage to be investigated. Encouraging results from the cell-based studies would in turn lead to testing of the synthetic proteins in pre-clinical models of PD, an essential step in the drug development process.
We were able to produce several versions of recombinant cell permeable parkin proteins. The parkin activities of the different recombinant parkins were assessed using in-vitro ubiquination assays and immunoassay using human cells. Depending on the sequence variations, the parkin activity and their ability to internalize and translocate to mitochondria varied. We were able to observe translocation of cell-permeable recombinant human parkin proteins to mitochondria but was unable to observe subsequent active clearance of mitochondria upon damage. Additional versions are being designed for further testing.
Professor and Scientific Director at Montreal Neurological Institute, McGill University
Location: Montreal, Quebec, Canada
Senior Scientist at iProgen Biotech, Inc.
Location: Richmond, British Co, Canada