For release: Friday, June 17, 2011
Families with Huntington's disease know the devastation it inflicts. The disease attacks parts of the brain essential for thinking and motor control, leading to dementia, personality changes, and uncontrolled movements. A lesser known and early symptom is unwanted weight loss. Scientists have long suspected, but could not prove, that the weight loss might reflect a metabolic problem – perhaps a breakdown of the cellular energy factories known as mitochondria.
Now, a study published in Nature Medicine* suggests that defects in the number, size and distribution of mitochondria play an early, critical role in Huntington's disease.
Mitochondria meet the ever-changing energy demands of a brain cell by staying fluid and mobile. They can move to different parts of the cell. They also can fuse to each other, stretch into long tubes and split apart again. The new study shows that this splitting process, known as mitochondrial fission, is enhanced in Huntington's disease. In cells affected by Huntington's disease, the mitochondria are fragmented and the degree of fragmentation correlates with disease severity. Moreover, these defects depend on the activity of a protein called DRP1, which could be a new target for drug therapies against the disease.
"Our study opens the door for a set of new and exciting investigations," said Ella Bossy-Wetzel, Ph.D., the study's senior author and an associate professor at the Burnett School of Biomedical Sciences of the University of Central Florida in Orlando.
Huntington's disease is hereditary, caused by mutations that affect a protein called huntingtin. Those mutations appear to render the protein toxic, particularly to cells in the striatum, a part of the brain that controls movement. Researchers do not understand what the normal huntingtin protein does or why mutant huntingtin is toxic. There is evidence that the mutant protein accumulates in garbage heaps that interfere with cell housekeeping, and that it alters gene expression.
Researchers have also theorized that huntingtin might regulate mitochondria. Besides weight loss, people with Huntington's disease show signs of reduced metabolic activity in the striatum. Just last year, one research team found a trend for smaller mitochondria in cells expressing the mutant huntingtin protein. Their data suggested that the cells were inefficient at making new mitochondria.
Dr. Bossy-Wetzel theorized that smaller, weaker mitochondria could also result from unchecked fission. She and her team examined skin cells from patients with Huntington's disease, and observed round fragmented mitochondria. They saw similar mitochondria in the brains of mice with Huntington's prior to disease onset. Next, they performed advanced imaging on these mice at the National Center for Microscopy and Imaging Research at the University of California, San Diego. Images of the mitochondrial cristae – membranes within mitochondria where energy is generated and other essential chemical reactions occur – revealed more evidence of fragmentation.
In other experiments, they watched as mitochondria fused, divided, and moved within brain cells. In cells with the mutant huntingtin protein, the mitochondria showed increased rates of fission and less ability to move to sites of high energy demand. Cells with the most severe huntingtin mutations had the worst mitochondrial defects and the worst rates of survival.
Dr. Bossy-Wetzel and her team suspected that huntingtin might cause these defects by acting through DRP1, an enzyme that triggers mitochondrial fission. They found that mutant huntingtin interacted strongly with DRP1 and increased its enzymatic activity. They also tested whether blocking DRP1 could block the effects of mutant huntingtin in brain cells. They found that giving the cells an inactive form of DRP1 helped restore the balance between mitochondrial fusion and fission, and improved cell survival.
These findings suggest that drugs targeting DRP1 could be beneficial in people with Huntington's disease. The inactive DRP1 protein, although beneficial in a cell model of Huntington's, probably could not be used as a drug because of the challenges of delivering it to patients' brain cells. However, there are small-molecule inhibitors of DRP1 that could serve as a starting point for drug development, Dr. Bossy-Wetzel said.
She and her team are currently investigating several of these DRP1 inhibitors in Huntington's disease models. They are also carrying out studies to better understand the interaction between huntingtin and DRP1, including the parts of each protein needed for them to connect.
"DRP1 has important functions, thus blocking its activity entirely may cause severe side effects," Dr. Bossy-Wetzel said. "Gaining insight into how mutant huntingtin interacts with DRP1 may allow the design of safe, specific therapeutics."
This research was funded by the National Institute of Neurological Disorders and Stroke, the National Eye Institute, the Hereditary Disease Foundation, The National Center for Research Resources, the Canadian Institutes of Health Research, and CHDI, Inc.
- By Daniel Stimson, Ph.D.
Image caption: Two views of mitochondrial fission caused by mutant huntingtin. At high magnification, in blue, is a single mitochondrion splitting into three, with its cristae labeled in multiple colors. At lower magnification in the background are many fragmented mitochondria, distributed throughout a brain cell. Image courtesy of Guy Perkins, Ph.D., National Center for Microscopy and Imaging Research, University of California, San Diego and Wenjun Song, University of Central Florida, Orlando.
*Song W et al. "Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity." Nature Medicine, March 2011, Vol. 17, pp. 377-382.
Last Modified June 23, 2011