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Two teams of researchers funded by the National MS Society have reported findings on nerve tissue injury and repair that add important information needed to stop MS progression and develop nervous system repair strategies. Isobel Scarisbrick, PhD (Mayo Clinic and Foundation, Rochester, MN) and colleagues have found two enzymes that may serve as markers of progressive MS and nerve fiber injury. Patrizia Casaccia, MD, PhD (Mount Sinai School of Medicine, New York) and colleagues reported that another enzyme is essential for replenishing myelin-making cells that have been depleted by MS. Both teams are continuing these lines of research in hopes of identifying targets for the development of new therapies for MS.
Dr. Scarisbrick reported her team’s findings related to MS progression at the annual meeting of the American Neurological Association (Abstract T-99). Dr. Casaccia’s report on the enzyme critical for repair appeared in Nature Neuroscience (early online publication, August 24, 2008).
Understanding the processes that lead totissue damagein MS is crucial to feed parallel efforts toprotect and repairthe brain and spinal cord. Dr. Scarisbrick previously found elevated levels of “KLK6” (a newly identified member of the kallikrein enzyme family) in areas of damage found in tissue samples from people with MS. Now, in a follow-up study, the group has studied the levels of KLK6 and other kallikreins in blood samples taken from 35 people with different clinical courses of MS and 62 controls without MS.
The results show that KLK1 and KLK6 were elevated in people with MS, with the highest levels appearing in people with secondary-progressive MS (a course of MS that initially is relapsing-remitting and then becomes progressive, with or without occasional relapses and minor remissions).
The team also exposed nerve cells isolated from mice to KLK1 or KLK6 in the laboratory, and found that the enzymes promoted nerve cell loss. Dr. Scarisbrick is continuing to study the role of these enzymes in nerve fiber injury and hopes to find a way to target them with therapeutic strategies for people with progressive MS.
MS involves immune attacks against brain and spinal cord tissues, primarily myelin, the insulation that surrounds and protects nerve fibers. Several studies have indicated that, early in the disease, immature myelin-making cells – called, “oligodendrocyte progenitors” – are recruited to generate new myelin. A sufficient number of these cells is needed so that progenitors can migrate to the site of myelin damage and develop into myelin-making cells. Then, genes that instruct the formation of myelin components are activated and myelin is formed. In MS, this process fails. Dr. Casaccia is studying whether some molecules may inhibit the activation of the genes that promote myelin formation.
In this study, Dr. Casaccia’s team observed the gene activity during oligodendrocyte development in mice with damaged myelin. They found that enzymes called histone deacetylases (HDACs) were crucial to this process, particularly HDAC1 and HDAC2. Deleting these two enzymes impaired the differentiation of oligodendrocyte progenitors, that is, the process by which these cells develop a more specialized form or function. The team is studying how these findings might be translated into therapeutic strategies.
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