For release: Tuesday, February 23, 2010
New studies supported by the National Institutes of Health shed light on the functions of two genes related to Parkinson’s disease called parkin and PINK1.
The studies connect parkin and PINK1 in a pathway that assures quality control over mitochondria – subcellular factories that are the main source of energy for neurons and most other cells in the body.
One study was led by Richard Youle, Ph.D., a senior investigator at NIH’s National Institute of Neurological Disorders and Stroke (NINDS). The other study was led by Serge Przedborski, M.D., Ph.D., a professor of neurology and pathology at Columbia University Medical Center in New York. This study was funded by NINDS, the National Institute on Aging (NIA), the National Institute of Environmental Health Sciences (NIEHS), the Department of Defense and non-profit foundations.
Parkinson’s disease attacks neurons in the substantia nigra, a part of the brain that helps control movement. The most common symptoms of the disease are involuntary shaking, slow movement, stiffened muscle tone, and impaired balance.
The vast majority of cases of Parkinson’s disease are sporadic, meaning the cause is unknown. About 5-10 percent of cases are caused by mutations in single genes, including parkin, PINK1, SNCA and others. Researchers believe that studying these genes will not only benefit patients with genetic Parkinson’s, but also will yield insights into what causes the sporadic disease. (Indeed, a recent study shows that SNCA is a risk factor for sporadic Parkinson’s.)
One theory holds that sporadic Parkinson’s involves a breakdown of the mitochondria, hammering neurons with a depletion of energy and a buildup of harmful byproducts (called oxidative stress). There is evidence of mitochondrial damage in the substantia nigra of patients. Also, the pesticides paraquat and rotenone can induce Parkinson-like symptoms in animal models, and are known to injure mitochondria. Still, many experts question whether mitochondrial damage is a cause or a consequence of Parkinson’s.
“By showing that parkin and PINK1 are involved in quality control of mitochondria, our data support the idea that mitochondrial damage can play a causative role in Parkinson’s disease,” said Dr. Youle.
Dr. Przedborski noted that “a similar dysfunction of mitochondria could occur even in the absence of a genetic defect. You can imagine that environmental factors or other non-genetic factors could cause mitochondrial damage over time and lead to Parkinson’s disease.”
Prior research had hinted that parkin and PINK1 are important for keeping mitochondria in working order. Cells deficient in either protein have abnormal mitochondria, but the reasons for this were not clear. Last year, Dr. Youle and his team reported that parkin is recruited to damaged mitochondria and that it stimulates their destruction.
The two new studies show that PINK1 is the signal for recruiting parkin. These data came in part from experiments in which the researchers exposed cells to mitochondrial toxins, and tracked the responses of fluorescent-tagged parkin. Parkin moved to the mitochondria damaged by the toxins, and this movement was dependent on PINK1. If the cells lacked PINK1, parkin failed to move to the mitochondria. Giving the cells extra PINK1 or (in Dr. Youle’s study) a version of PINK1 that sticks tightly to all mitochondria – even healthy ones – increased recruitment of parkin to the mitochondria and led to their destruction.
Both research teams confirmed that this pathway is relevant to Parkinson’s disease by showing that several PINK1 and parkin mutations found in patients have adverse effects on parkin recruitment and/or mitochondrial turnover.
One goal of future research is to determine exactly how PINK1 and parkin work together to target mitochondria for destruction. Not all the steps in this process are understood, and there may be other proteins that help PINK1 and parkin interact, the researchers said. A complete understanding of the PINK1-parkin pathway could lead to drug therapies that tip the balance toward healthy mitochondria.
Dr. Youle’s study was published in PLoS Biology*. Other key authors included Derek Narendra, a graduate student in the NIH-Cambridge Biomedical Research Scholars program, and Mark Cookson, Ph.D., an investigator in the Laboratory of Neurogenetics at NIA. Dr. Przedborski’s study was published in Proceedings of the National Academy of Science**. Other key authors included Cristofol Vives-Bauza, Ph.D., Chun Zhou, M.D., Ph.D., and Yong Huang, M.D., Ph.D., of Columbia University; Ted Dawson, M.D., Ph.D., and Valina Dawson, Ph.D., both professors of neurology and neuroscience at the Johns Hopkins University in Baltimore. Dr. Dawson is the Director of the Morris K. Udall Parkinson’s Disease Research Center of Excellence at Johns Hopkins.
- By Daniel Stimson, Ph.D.
*Narendra DP et al. “PINK1 is Selectively Stabilized on Impaired Mitochondria to Activate Parkin.” PLoS Biology, January 26, 2010, Vol. 8(1), e1000298.
**Vives-Bauza C et al. “PINK1-Dependent Recruitment of Parkin to Mitochondria in Mitophagy.” Proceedings of the National Academy of Science, January 5, 2010, Vol. 107(1), pp. 378-83.
Last Modified February 23, 2010