Excitotoxic neuronal injury occurs following brain insults such as cerebral ischemia. Since stroke affects over 4.5 million Americans targeting of excitotoxicty represents a key therapeutic priority. A second priority is Alzheimer's disease which afflicts a similar number of American. Although less common than stroke and Alzheimer's, the demyelinating disease multiple scleroris is none the less a serious and difficult to treat disease. Recently published research emerging from Florida State University, and in collaboration with the Mayo Clinic, Rochester has advanced our progress towards possible treatments of each of these conditions. This research focuses on myelencephalon-specific protease. As suggested by the name this serine protease was first described as a brain specific enzyme although of interest high levels of it's human equivalent human kallikrein 6 (also known as Zyme, protease M and neurosin) have also been reported in ovarian and breast carcinomas. Levels are particularly high in the medulla oblongata and the white matter of the spinal cord, and were found to increase in a model of excitotoxic injury. Human kallikrein 6 was found in neurons in the gray matter and glia in the white matter of patients with Alzheimer's disease. Levels in grey matter are reduced, whilst levels of inactive precursors in the spinal cord and plasma are increased. It has been suggested that reduced levels of Human kallikrein 6 in grey matter may prevent breakdown of disease causing beta amyloid 42. Finally myelencephalon-specific protease was found in oligodendrocytes and this suggested a possible role in myelination. Florida State researchers have now developed an expression system able to probe the enzyme activity of myelencephalon-specific protease. Using this assay system they show that enzymatic activity is turned on by additional enzymes and innactivated through autolysis. In it's activated form myelencephalon-specific protease is able to degrade myelin-associated as well as several extracellular matrix proteins. Furthermore it is abundantly expressed in inflammatory cells at sites of demyelination in the Theiler's murine encephalomyelitis virus model of multiple sclerosis. The consensus opinion is therefore that inhibitors of human kallikrein 6 may be able to reduce diseases such as stroke and multiple sclerosis. On the other hand, increasing levels of this enzyme may be able to clear beta amyloid. Thus inhibitors of enzyme activity or it's autolytic deactivation may be of immense therapeutic use. The in vitro assay system developed by this group should allow the high-throughput screening for such molecules and hits can be conveniently tested in their in vivo models. Collaborations are therefore sought to expedite this process.

Enzymatic Properties of Rat Myelencephalon-Specific Protease

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