A link between two proteins known to cause Parkinson’s disease has been found by researchers from Johns Hopkins Medicine, Baltimore, MD, in collaboration with researchers at the Mayo Clinic, Jacksonville, FL. They have published their results in the January 24 issue of Cell Reports, and suggest that someday, a single treatment targeted for this link could neutralize both proteins.
Previous researchers found that when a protein known as PARIS, involved in the Parkinson’s process, was reduced in mice with the rodent equivalent of Parkinson’s disease, the result was protection against the loss of dopamine-producing neurons.
Mutations in the gene for the Parkin protein cause death in dopamine neurons, as can defects in PINK1—another protein—although this occurs less commonly. Classic Parkinson’s symptoms, including tremor, muscle stiffness, loss of coordination, are known to be caused by dopamine depletion.
Thus, Ted Dawson, MD, PhD, professor, neurology, and director, Institute for Cell Engineering, Johns Hopkins University School of Medicine, and colleagues conducted this study to test their suspicion that PARIS may be chemically linked to other Parkinson’s proteins.
To assess the possible relationship between PINK1 and PARIS, Dawson et al. conducted biochemical tests on purified proteins, and found an interaction.
According to Dr. Dawson, their results showed that while the normal role of PINK1 is to add a chemical tag (a phosphate group) to a specific location on the PARIS protein, defective PINK1 linked to Parkinson’s disease could not add that chemical tag.
By reducing PINK1 amounts in lab-grown human cells, they cause a 3-fold increase in the amount of PARIS, confirming that the addition of phosphate initiates a chain of events ultimately concluding in the dismantling of the PARIS protein.
Next, they found that by reducing amount of PINK1 made by living mice by over 80%, levels of PARIS doubled. Finally, by increasing production of PINK1 in lab-grown human cells, they could alleviate the increase in cell death that resulted by increasing levels of PARIS. But, when PINK1 was manipulated to eliminate the sites where PARIS normally adds a phosphate group, PARIS did not alleviate cell death.
Thus, they concluded, PINK1 may actually prime Parkin-mediated ubiquination of PARIS in dopaminergic neuronal survival, and both Parkin and PINK1 both protect brain cells by causing the breakdown of PARIS. Dr. Dawson noted that the defects in both may be remedied if a treatment to hobble PARIS could be found.
“Mutations in the genes for both Parkin and PINK1 have now been linked to Parkinson’s disease,” he said. “Parkin is a particularly big player that seems to be at fault in many inherited cases; it’s also inactivated in sporadic cases of the disease. So a drug targeting PARIS could potentially help many patients.”
But, he cautioned, clinical application of these results needs further study.
This work was supported by grants from the National Institute of Neurological Disorders and Stroke (grant numbers NS38377 and R01 NS085070), the JPB Foundation, the Samsung Biomedical Research Institute, the Michael J. Fox Foundation for Parkinson’s Research and the Foundation for Mitochondrial Medicine, the Mayo Clinic Foundation, the Centers for Individualized and Regenerative Medicine, the Marriott Family Foundation, a Gerstner Family Career Development Award, a fellowship from the American Parkinson Disease Association, the National Research Foundation of Korea (grant numbers NRF-2016R1A2B4008271 and 2015R1C1A1A01052708) and a Samsung Biomedical Research Institute grant (grant numbers SMX1161351 and SMX1161191). The authors acknowledge the joint participation by the Adrienne Helis Malvin Medical Research Foundation and the Diana Helis Henry Medical Research Foundation through their direct engagement in the continuous, active conduct of medical research in conjunction with The Johns Hopkins Hospital, the Johns Hopkins University School of Medicine and the Foundation’s Parkinson’s Disease Programs M-1, M-2, H-2014. T. Dawson is the Leonard and Madlyn Abramson Professor of Neurodegenerative Diseases.
Research discussed in this publication involves technology that Ted and Valina Dawson anticipate Valted, LLC may own or license in the future. Ted and Valina Dawson are founders of Valted, LLC and hold ownership equity interest in the company. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies.