Novel Technique Reveals New Targets for PARKINSON’S DISEASE
Four genes that serve as “helper genes” to the parkin protein have been discovered using an innovative screening method. The discovery of these genes will lead to more targets for research and development of potentially new drugs treatment of PARKINSON’S DISEASE. The researchers from the National Institutes of Neurological Disorders (NINDS) and the National Center for Advancing Translational Sciences (NCATS) were recently published in the on-line journal, Nature.
Parkin has long been studied and is known to be one agent that marks the damaged mitochondria for destruction. Mitochondria are the tiny energy sources that cells depend on to function. Normal parkin marks these damaged mitochondria for destruction and replacement but when the gene that codes for parkin protein becomes mutated, the damaged mitochondria build up and are not recycled, which causes even more damage to the cells. This mitochondrial dysfunction is notable in PARKINSON’S DISEASE and other neurological movement disorders.
RNAi (RNA interference) has been used since it was developed in 1998. It has proven useful to researchers in understanding how genes function. Using this technique, investigators inserted small interfering RNA (siRNA) into human cells, which enabled them to turn nearly 22,000 genes off. They were then able to screen by automated microscopy exactly how each gene affected parkin’s ability to tag mitochondria that were damaged. They found four such genes.
When they switched off two of those genes, parkin was unable to tag any damaged mitochondria. When they switched off two other genes, parkin performed even better. These genes are known to regulate proteins found in mitochondria.
Next, they developed a human nerve cell from an induced pluripotent cell from human skin. They tested one of the genes, called TOMM7 on these cells and found that turning it off caused parkin to also stop tagging mitochondria. After even more experiments, they are calling these four genes “helper genes” and hope that they will serve to develop new targets for better understanding of PARKINSON’S DISEASE and also for developing new drugs. “We have discovered a network of genes that may regulate the disposal of dysfunctional mitochondria, opening the door to new drug targets for PARKINSON’S DISEASE and other disorders”, said Dr. Richard Youle, one of the researchers on this study. His co-collaborator was Dr. Scott Martin.
Samuel A. Hasson, Lesley A. Kane, Koji Yamano, Chiu-Hui Huang, Danielle A. Sliter, Eugen Buehler, Chunxin Wang, Sabrina M. Heman-Ackah, Tara Hessa, Rajarshi Guha, Scott E. Martin, Richard J. Youle. High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy. Nature, 2013; DOI: 10.1038/nature12748
Review by Marcia McCall