Research Highlights

UC San Diego's National Center for Microscopy and Imaging Research (NCMIR) Instrumental in Huntington's Disease Breakthrough

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Figure: Foreground: A 3D reconstruction of a fissioning mitochondrion found in a neuronal process in the striatal brain region of a huntingtin mutant mouse exhibits the process of fragmentation into three bodies. The outer membrane (blue) shows constrictions between the three bodies. The cristae are shown in various colors. The background is a huntingtin mutant cultured neuron showing the fluorescently labeled (grey) fragmented mitochondria. The fragmentation is seen not only in the neuronal cell body (large concentration of grey dots), but also in the neuronal processes (lines of grey dots extending from the cell body).

March 2011 La Jolla

Imagine being able to prevent certain death of nerve cells in the brain and visualizing the feat with the latest in electron microscope technology.  That’s just what a team of biomedical researchers did, including UC San Diego’s own National Center for Microscopy and Imaging Research (NCMIR), giving hope to Huntington’s disease patients. 

Huntington’s disease is an inherited and incurable neurodegenerative disorder affecting 35,000 people annually and is caused by mutation of the gene encoding the huntingtin protein. The disease gradually kills nerve cells in the brain, stripping away a person’s muscle coordination and causing hallucinations, antisocial behavior and paranoia. People diagnosed with Huntington’s disease usually die 15 to 20 years from the onset of symptoms, and there is an increased rate of suicide among those struggling with the disease.

Laboratory tests on skin cells and post-mortem brain tissue of Huntington’s disease patients found that mutant huntingtin abnormally stimulates another protein to trigger a chain reaction that causes brain nerve cells to die. Reducing the activity of that protein, known as DRP1 and associated with mitochondria—the cell’s power plant--prevented the chain reaction and kept those cells alive, according to the research team led by University of Central Florida professor Ella Bossy-Wetzel.

To see how mitochondria responded to overactive DRP1, NCMIR employed cutting edge electron tomography to provide the highest resolution, three-dimensional imaging available of the mitochondria affected by mutant huntingtin protein.  Led by Drs. Guy Perkins and Mark Ellisman , NCMIR researchers used a JEOL 4000FX high-voltage electron microscope with increased penetration power to image larger volumes of brain tissue. They showed that mutant huntingtin triggers increased mitochondrial fission and defects in its transport in isolated neurons and Huntington’s disease mice before the presence of neurological deficits and mutant huntingtin aggregates. Only through the use of this high-resolution imaging technology were researchers able to show that mutant huntingtin also causes cristae fragmentation and loss, thus impacting a neuron’s survival rate. “Upon examining the volumes generated by tomography, we realized that we had captured mitochondria at various stages in the fissioning process and noted how the cristae membranes housing the energy-producing machinery inside mitochondria were being remodeled,” Guy Perkins said.  “It still amazes me that we use instruments allowing us to see changes in tiny biological compartments that are about 10,000 times smaller than a grain of sand.” Reducing DRP1 activity significantly slowed neuronal cell death and might represent a new therapeutic target to combat neurodegeneration in Huntington’s Disease patients.

“The next step will be to test the DRP1 function in animals and patients to see whether the protein also protects the brain,” Bossy-Wetzel said. “This could be done before the onset of disease in patients who have the mutant Huntington gene, but have no neurological symptoms. The hope is that we might be able to delay the onset of disease by improving the energy metabolism of the brain.”

The research was led by Ella Bossy-Wetzel of the University of Central Florida, and included collaborative research teams from UC San Diego’s National Center for Microscopy and Imaging Research (NCMIR), the University of Salzburg, Austria, the University of British Columbia, Canada, and McGill University, Canada.

The research findings were published online in the journal Nature Medicine and are featured in the cover story of the March edition.

(Adapted from materials provided by the University of Central Florida)

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