DRP1 is Identified as a Promising Therapeutic Target

Impaired energy metabolism has been shown to be a major pathology in  Huntington's disease.  The mitochondria, the cell's energy factories,  have not been found to be  intrinsically defective but are thought to be  mismanaged in some way.  A University of Central Florida research team  lead by Dr. Ella Bossy-Wetzel has discovered how this occurs.  The HD  protein interacts abnormally with the mitochondrial fission GTPase  dynamin-related protein-1 (DRP1).  DRP1 is the protein that is  responsible for mitochondria fission in the fission-fusion cycle.  DRP1  becomes overactive and upsets the balance in the cycle.  The  mitochondria fragment, mitochondrial transport becomes impaired, and  cells die.

The researchers first examined rat cortical cells.  Those with a  normal polyglutamine region had healthy mitochondria whereas those with  expanded polyglutamine stretches (expanded CAG repeats) had fragmented  mitochondria.  Those with 97 CAG repeats had more fragmentation than  those with 46 CAG repeats.  Time lapse imaging showed an increase of  fission events compared to fusion events.  Fragmentation was correlated  with cell death.

Human skin cells were next examined.  Fragmentation was also found in  cells from people with Huntington's disease, more so in those with  juvenile rather than adult onset.

In addition, the researchers also examined mitochondrial transport  and velocity in the rat cortical cells.  Transport and velocity were  normal when the CAG repeats were normal but decreased with expanded  repeats.  Again, the impairment was more severe with higher repeats.   This is important because decreased transport would likely have a  negative effect on energy distribution especially at synapses where  demand for energy is high.

The researchers confirmed their findings in the YAC128 mice, finding  an increase in mitochondrial fragmentation before the onset of symptoms,  neurological deficits, aggregate formation, and cell death.

The researchers next examined the possible role of DRP1 in  fragmentation.  Examining both the YAC128 mice, and human brain tissue,  they found that while the normal huntingtin protein only weakly  interacts with DRP1 at best, the HD protein binds to DRP1 and increases  its enzymatic activity.

Finally, they found that restoring the normal fission-fusion cycle by  replacing DRP1 with a mutant version (DRP1 K38A) which promotes fusion,  they were able to rescue the cell from mitochondrial fragmentation,  mitochondrial transport impairment, and cell death.

"The next step will be to test the DRP1 function in animals and  patients to see whether the protein also protects the brain," Dr.  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."

"It is an outstanding piece of work, which further implicates  mitochondrial dysfunction in the pathogenesis of Huntington's disease,"  said Dr. Flint Beal, a professor of neurology and neuroscience at the  Weill Medical College of Cornell University who specializes  in the  disease and is a practicing physician. "It opens new therapeutic targets  for therapies aimed at disease modification."

Reference:

University of Central Florida press release

Marsha Miller, Ph.D.
Dr. Ella Bossy-Wetzel and colleague (Photo by Jacque Brund)
Dr. Ella Bossy-Wetzel and colleague
(Photo by Jacque Brund)
Mutant huntingtin-mediated mitochondrial fragmentation, defects in anterograde and retrograde mitochondrial transport and neuronal cell death are all rescued by reducing DRP1 GTPase activity

Wenjun Song, Jin Chen, Alejandra Petrilli, Geraldine Liot, Eva Klingmayr, Yue Zhou, Patrick Poquiz, Jonathan Tjong, Mahmoud A. Pouladi, Michael R. Hayden, Eliezer Masliah, Mark Ellisman, Isabelle Rouiller, Robert Schwarzenbacher, Blaise Bossy, Guy Perkins, & Ella Bossy-Wetzel

abstract:

Huntington's disease is an inherited and incurable neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in huntingtin (encoded by HTT). PolyQ length determines disease onset and severity, with a longer expansion causing earlier onset. The mechanisms of mutant huntingtin-mediated neurotoxicity remain unclear; however, mitochondrial dysfunction is a key event in Huntington's disease pathogenesis. Here we tested whether mutant huntingtin impairs the mitochondrial fission-fusion balance and thereby causes neuronal injury. We show that mutant huntingtin triggers mitochondrial fragmentation in rat neurons and fibroblasts of individuals with Huntington's disease in vitro and in a mouse model of Huntington's disease in vivo before the presence of neurological deficits and huntingtin aggregates. Mutant huntingtin abnormally interacts with the mitochondrial fission GTPase dynamin-related protein-1 (DRP1) in mice and humans with Huntington's disease, which, in turn, stimulates its enzymatic activity. Mutant huntingtin-mediated mitochondrial fragmentation, defects in anterograde and retrograde mitochondrial transport and neuronal cell death are all rescued by reducing DRP1 GTPase activity with the dominant-negative DRP1 K38A mutant. Thus, DRP1 might represent a new therapeutic target to combat neurodegeneration in Huntington's disease.

Nature Medicine 2011 Feb 20. [Epub ahead of print]