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Therapeutic Strategy for Huntington’s Disease Could Focus on Containing Cell ‘Shrapnel’

For release: Wednesday, November 24, 2010

Photos showing a normal fly retina, the degenerating retina of a fly with Huntington’s disease and the same model rescued by deficiency of the MMP gene.

Writing in the journal Neuron,* investigators report that enzymes involved in ailments from stroke to cancer also play a role in Huntington’s disease.  Blocking the function of these enzymes, called matrix metalloproteinases (MMPs), is beneficial in cell and animal models of Huntington’s, and could be an effective therapeutic strategy for patients.

Huntington’s disease is genetic and usually strikes in middle age, leading to uncontrollable movements of the legs and arms, a loss of muscle coordination, and changes in personality and intellect.   These symptoms are caused by a loss of neurons in the striatum and in other parts of the brain that control movement.  The disease worsens over time, and is usually fatal within 20 years of onset.  There is currently no therapy to slow its course.

The mutations at the root of Huntington’s disease change the shape of a protein called huntingtin, making it longer, bulkier and toxic to brain cells.  In a protective response, the cells deploy enzymes to break apart the mutant protein.  But there is evidence that like the shrapnel from an explosion, the smallest pieces of the protein may be the most harmful.

Lisa Ellerby, Ph.D. and Robert Hughes, Ph.D., investigators at the Buck Institute for Age Research in Novato, California, led an effort to search for the key enzymes involved in generating the smallest, most toxic huntingtin fragments.  There are more than 500 protein-cutting enzymes, or proteinases, in human cells.  The research team grew cells that were engineered to make the mutant huntingtin protein, and then used a strategy called RNA interference to block the function of 514 known proteases, one by one.  They then monitored the huntingtin fragments produced by the cells.

Using this unbiased screen – in other words, checking all 500-plus enzymes rather than trying to guess the important ones – enabled the team to “discover a role for novel proteinases that had not previously been investigated in Huntington’s research,” Dr. Ellerby said.  The team found 11 enzymes, including three in the MMP family, that are essential for generating the smallest bits of mutant huntingtin.

In a secondary screen, the team asked how these 11 enzymes affect the toxicity of mutant huntingtin in mouse brain cells.  They found they could reduce signs of toxicity and cell death when they used RNA interference to individually turn off nine of the enzymes, including the three MMPs.

Humans have about 30 different MMPs.  Although MMPs have beneficial roles in tissue growth and repair, some have been shown to contribute to cancer and stroke.  In cancer, for example, MMP-14 appears to degrade the connective tissue surrounding cancer cells enabling them to spread with brutal efficiency.  In stroke, MMP-9 is thought to weaken the blood-brain barrier, a network of capillaries that normally shields the brain from toxins and infections in the blood.  This research has led to large investments in drugs that are capable of inhibiting MMPs.  While many of the inhibitors available today interfere with the normal functions of MMPs, drug companies are working toward more precise inhibitors that target only the harmful effects of the proteins.

In their study, Dr. Ellerby and her colleagues found that MMP-10 and MMP-14 seem to be the key members of the MMP family involved in the breakdown of mutant huntingtin.   Levels of both these MMPs are increased in mouse brain cells that express the mutant protein.  Meanwhile, a chemical inhibitor of MMP-10 reduced the mutant protein’s toxicity in these cells.

Next, in collaboration with Juan Botas, Ph.D., at Baylor College of Medicine in Houston, Dr. Ellerby asked if genetically knocking down MMP activity could rescue a fruit fly model of Huntington’s disease.  These flies carry the same kind of huntingtin mutations found in patients and develop clear motor impairments.  While humans have dozens of MMP genes, fruit flies have just one that is active in the adult brain, which simplified these experiments.  When given a defective copy of the MMP gene, the mutant flies showed better motor control.

In another fly model of Huntington’s disease, the mutant huntingtin protein is targeted to the fly eye, which causes neurons within the fly retina to degenerate.  Dr. Ellerby and her team showed that a genetic deficiency of MMP enhanced the survival of retinal neurons in this model.

The team is beginning to evaluate whether genetic or pharmacological inhibition of MMPs is beneficial in mouse models of Huntington’s disease.

The research was funded by the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the CHDI Foundation and the Huntington’s Disease Foundation.

-By Daniel Stimson, Ph.D.

*Miller JP et al.  “Matrix metalloproteinases are modifiers of huntingtin proteolysis and toxicity in Huntington’s disease.”  Neuron, Vol. 67, pp. 199-212, July 29, 2010.

Photos showing a normal fly retina, the degenerating retina of a fly with Huntington’s disease and the same model rescued by deficiency of the MMP gene.
A normal fly retina (left) compared to the retina in a fly model of Huntington’s disease (middle) and the same model partially rescued by a deficiency of the MMP gene (right). The arrows point to the surface of each retina and also show the retina’s thickness. From Miller JP et al., Neuron, July 2010.

Last Modified November 30, 2010