Drp1 Protein Linked to Parkinson's Disease

Research led by California Nanosystems Institute (CNI) has shed new light on mechanisms controlling protein Drp1—a regulator of mitochondrial fission—and suggest that interventions targeting the signaling pathway are a potential therapeutic target for Parkinson’s Disease.

An emerging school of Parkinson’s research has focused on mitochondria—structures within cells that make energy—and how errors that reduce mitochondrial fission may contribute to development of the neurodegenerative disease.  Dysfunction in Drp1, already known to be a master regulator of mitochondrial fission, has been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease.

Now, a research collaboration led by CNI and published recently in Nature Communications has found that a protein in humans called CLUH acts to attract Drp1 to mitochondria and trigger fission. In experiments with fruit flies that were genetically engineered with an analog for Parkinson’s disease, the team showed that damage from the disease could be reversed by increasing the amount of a protein that scientists call “clueless,” which is the fruit fly equivalent of CLUH.

“With a critically important pathway such as Drp1, there might be multiple proteins we could use to intervene and ultimately control Parkinson’s disease,” says Dr. Ming Guo, the corresponding author of the study. “When we modified clueless in flies, symptoms analogous to Parkinson’s disease improved substantially.”

Guo and her colleagues found that loss of clueless (in the fruit flies) or CLUH (in the human cells) resulted in mitochondria that appeared to be longer, while large amounts of clueless or CLUH proteins resulted in fragmented mitochondria. Guo said the longer mitochondria likely result from too little fission, and the fragmented ones from too much fission.

Fruit flies that had been genetically engineered to lack clueless—a manipulation that dramatically shortens their lifespans—lived up to nearly four times as long when the researchers administered more Drp1 protein. The findings suggest that clueless’s ability to control mitochondrial fission works through Drp1.

The team further showed that both clueless in flies and CLUH in human cells recruit free-floating Drp1 from within a cell to attach to receptors on the surface of mitochondria. They also found that CLUH in human cells helps translate the genetic instructions found in messenger RNA into the protein for Drp1 receptors on the surface of mitochondria. More available Drp1 receptors means that more Drp1 can be recruited in order to trigger fission.

“In the future, we hope to identify a mechanism with such precision that it only affects Parkinson’s disease, so patients can derive maximum benefit,” Guo said.