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

July 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.

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

Related Stories

Recommended for you

Gene mutation causes low sensitivity to pain

December 13, 2017
A UCL-led research team has identified a rare mutation that causes one family to have unusually low sensitivity to pain.

Activating MSc glutamatergic neurons found to cause mice to eat less

December 13, 2017
(Medical Xpress)—A trio of researchers working at the State University of New York has found that artificially stimulating neurons that exist in the medial septal complex in mouse brains caused test mice to eat less. In ...

Scientists discover blood sample detection method for multiple sclerosis

December 13, 2017
A method for quickly detecting signs of multiple sclerosis has been developed by a University of Huddersfield research team.

LLNL-developed microelectrodes enable automated sorting of neural signals

December 13, 2017
Thin-film microelectrode arrays produced at Lawrence Livermore National Laboratory (LLNL) have enabled development of an automated system to sort brain activity by individual neurons, a technology that could open the door ...

Intermittent fasting found to increase cognitive functions in mice

December 12, 2017
(Medical Xpress)—The Daily Mail spoke with the leader of a team of researchers with the National Institute on Aging in the U.S. and reports that they have found that putting mice on a diet consisting of eating nothing every ...

Discovery deepens understanding of brain's sensory circuitry

December 12, 2017
Because they provide an exemplary physiological model of how the mammalian brain receives sensory information, neural structures called "mouse whisker barrels" have been the subject of study by neuroscientists around the ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.