Protease associated with damage after stroke implicated in Huntington's toxicity

Jul 28, 2010

A new study reveals that an enzyme linked with multiple disorders is also involved in the generation of toxic, neuron-killing protein fragments in Huntington's disease (HD). The research, published by Cell Press in the July 29 issue of Neuron, provides insight into Huntington's pathology and proposes new therapeutic strategies for this devastating incurable disease.

HD is an inherited disease that is characterized by degeneration of in the striatum and cortex. Symptoms of HD include uncontrolled movements, emotional disturbances, and mental deterioration. HD is caused by abnormal (Htt), and previous research has shown that it is small fragments of mutant Htt that are the most toxic for cells.

"A number of proteases, enzymes that cleave proteins, have been shown to work on mutant Htt," explains senior study author, Dr. Lisa M. Ellerby from the Buck Institute for Age Research. "While it has been suggested that cathepsins and/or calpains are the proteases responsible for producing the smallest and most harmful fragments, the exact cleavage sites and identity of the proteases involved have not been unequivocally identified."

Dr. Ellerby, along with coauthor Dr. Robert E. Hughes and colleagues, designed a sophisticated screen to examine the generation of the smallest Htt fragments. "Our screen identified 11 proteases that, when inhibited, reduced Htt fragment accumulation," explains Dr. Hughes. "Three of these belonged to the matrix metalloproteinase (MMP) family." MMPs have been implicated in a diverse collection of pathological processes, including , cardiovascular disease, cancer, and neuronal cell death after a stroke.

The researchers went on to show that one specific family member, MMP-10, directly cleaved Htt and that reduction of MMP prevented cell death in cultured striatal cells. Further, MMP activity was significantly elevated in mouse models of HD and reduced MMP activity reduced Htt-induced neuronal dysfunction in fruit flies.

Based on their findings, the researchers suggest that MMP family members should be considered as rational targets for developing novel HD therapeutics. "Our results suggest that general inhibition of MMPs may be of therapeutic benefit in Huntington's disease and that specific inhibitors of MMP-10 may be particularly relevant to disease treatment," concludes Dr. Ellerby.

Explore further: Researchers track down cause of eye mobility disorder

More information: Miller et al.: “Matrix Metalloproteinases Are Modifiers of Huntingtin Proteolysis and Toxicity in Huntington’s Disease.” Publishing in Neuron 67, 199-212, July 29, 2010. DOI 10.1016/j.neuron.2010.06.021

add to favorites email to friend print save as pdf

Related Stories

Protecting the brain from a deadly genetic disease

Feb 23, 2010

Huntington's disease (HD) is a cruel, hereditary condition that leads to severe physical and mental deterioration, psychiatric problems and eventually, death. Currently, there are no treatments to slow down or stop it. ...

Study suggests new treatments for Huntington's disease

Jan 09, 2008

Working with fruit flies, researchers have discovered a new mechanism by which the abnormal protein in Huntington’s disease causes neurodegeneration. They have also manipulated the flies to successfully suppress that neurodegeneration, ...

Recommended for you

Researchers track down cause of eye mobility disorder

10 hours ago

Imagine you cannot move your eyes up, and you cannot lift your upper eyelid. You walk through life with your head tilted upward so that your eyes look straight when they are rolled down in the eye socket. ...

How kids' brain structures grow as memory develops

11 hours ago

Our ability to store memories improves during childhood, associated with structural changes in the hippocampus and its connections with prefrontal and parietal cortices. New research from UC Davis is exploring ...

User comments : 0

More news stories

Down's chromosome cause genome-wide disruption

The extra copy of Chromosome 21 that causes Down's syndrome throws a spanner into the workings of all the other chromosomes as well, said a study published Wednesday that surprised its authors.

Simplicity is key to co-operative robots

A way of making hundreds—or even thousands—of tiny robots cluster to carry out tasks without using any memory or processing power has been developed by engineers at the University of Sheffield, UK.

Progress in the fight against quantum dissipation

(Phys.org) —Scientists at Yale have confirmed a 50-year-old, previously untested theoretical prediction in physics and improved the energy storage time of a quantum switch by several orders of magnitude. ...