Thwarting killer enzymes of the brain.Caspases are cellular executioners. Activated by damaged cells trying to commit suicide, these enzymes facilitate death by breaking up a variety of proteins. Two recent studies suggest that caspases play a crucial role in the death of brain cells observed in Huntington's disease Huntington's disease, hereditary, acute disturbance of the central nervous system usually beginning in middle age and characterized by involuntary muscular movements and progressive intellectual deterioration; formerly called Huntington's chorea. . One study even shows that inhibiting caspases can slow the development of symptoms and delay death in mice that have an illness that mimics the human neurodegenerative disorder neurodegenerative disorder Neurology A chronic progressive neuropathy characterized by selective and generally symmetrical loss of neurons in motor, sensory, or cognitive systems Types by area Cerebral cortex–Alzheimer's disease, Pick's disease, Lewy body . In the March Neuron, Junying Yuan of Harvard Medical School Harvard Medical School (HMS) is one of the graduate schools of Harvard University. It is a prestigious American medical school located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts. in Boston and her colleagues report that certain features of the mutant proteins made in Huntington's disease, so-called polyglutamine repeats, help activate one of the many caspases found in mammalian cells. Rat brain cells containing proteins with such repeats ultimately commit suicide. The repeats, consisting of multiple copies of the amino acid amino acid (əmē`nō), any one of a class of simple organic compounds containing carbon, hydrogen, oxygen, nitrogen, and in certain cases sulfur. These compounds are the building blocks of proteins. glutamine glutamine (gl  `təmēn), organic compound, one of the 20 amino acids commonly found in animal proteins. , convert caspase-8 into an active form, according to test tube studies performed by the researchers. A caspase inhibitor added to brain cells containing these repeats prevented the cells from dying, says Yuan. Her group has also shown that the affected brain regions of people with Huntington's disease do indeed contain activated caspase-8. A second study, in the May 20 NATURE, highlights a different caspase. Robert M. Friedlander of Brigham and Women's Hospital Brigham and Women's Hospital (BWH) is a hospital in the Longwood Area of the Boston, Massachusetts neighborhood of Mission Hill. With Massachusetts General Hospital, it is one of the two founding members of Partners HealthCare. in Boston and his colleagues worked with mice harboring a gene for an inhibitor of caspase-1. They bred these animals with mice having part of the mutant human gene that causes Huntington's disease. The latter mice usually develop disease symptoms, such as movement disorders Movement Disorders Definition Movement disorders are a group of diseases and syndromes affecting the ability to produce and control movement. Description and loss of brain and body weight, within 2 months of birth. The crossbred crossbred progeny of a mating between two animals which are purebreds of different breeds, e.g. crossbred sheep are usually offspring of matings between merinos and British breeds. mice didn't develop such problems until several weeks later. Friedlander's group also injected a caspase-1 inhibitor into the brains of the Huntington's-disease mice. They developed symptoms more slowly and survived longer than untreated mice did. "This is the first drug that can slow disease progression in a real mouse model of Huntington's," says Christopher A. Ross, who studies Huntington's disease at the John Hopkins Medical Institutions in Baltimore. If the drug similarly helps people with the disease, they might live 30 years after symptoms emerge rather than the usual 15 to 20, Friedlander calculates. The caspase-1 inhibitor used by Friedlander's team can act on other caspases, which may link the two groups' efforts. "The two papers together are quite interesting. They don't exactly add up to a clear story, but they do say that caspases are involved in more ways than we appreciated," comments Ross. Pharmaceutical companies are now racing to develop safer, more potent caspase inhibitors. The caspase-1 inhibitor employed in the mouse study has caused severe heart problems when tested on dogs for another illness. Caspase inhibitors may also tackle conditions ranging from strokes to Alzheimer's disease Alzheimer's disease (ăls`hī'mərz, ôls–), degenerative disease of nerve cells in the cerebral cortex that leads to atrophy of the brain and senile dementia. . "The lessons we learn in Huntington's disease, of how to slow down the caspase pathway, can also be used for other diseases," says Friedlander. |
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