Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myelencephalon-specific protease (MSP), first identified in the rat and now known to have a human homologue (human kallikrein 6), is preferentially expressed in the central nervous system (CNS), compared with nonneural tissues. MSP has been postulated to have trypsin-like activity, is upregulated in response to glutamate receptor-mediated excitotoxic injury in the CNS, and is downregulated in the brain of Alzheimer's patients. The preferential expression of this enzyme by oligodendrocytes in CNS white matter points to a role in myelin homeostasis. To further characterize the activity and substrate specificity of this newly identified enzyme, we have heterologously expressed MSP in a baculovirus/insect cell line system. We demonstrate that recombinant MSP exhibits a broad specificity for cleavage after arginine but not lysine residues, with kinetic characteristics intermediate between trypsin and pancreatic kallikrein. We show that the pro form of MSP does not self-activate but, rather, requires cleavage after lysine, indicating that mature active MSP is regulated by a distinct protease. MSP may be regulated in part by autolysis, since the active protein is readily inactivated through autolysis at specific internal arginine positions. Additionally, we show that MSP is abundantly expressed in inflammatory cells at sites of demyelination in the Theiler's murine encephalomyelitis virus (TMEV) model of multiple sclerosis (MS). In conjunction with data demonstrating the ability of MSP to degrade myelin-associated as well as several extracellular matrix proteins, these findings delineate MSP as a broad-specificity arginine-specific protease with the potential to play a key role in immune-mediated demyelination.
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PMID:Enzymatic properties of rat myelencephalon-specific protease. 1180 15

To determine the possible involvement of protease M/neurosin in demyelinating diseases of the CNS, we examined its expression in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), a recognized animal model of multiple sclerosis (MS). In situ hybridization, immunohistochemistry and quantitative real-time polymerase chain reaction (PCR) demonstrated that EAE caused an increase in the expression of protease M/neurosin mRNA and its protein product throughout the white and gray matter surrounding demyelinating lesions. Combined in situ hybridization and immunohistochemistry demonstrated that most of the cells expressing protease M/neurosin mRNA within control spinal cord showed immunoreactivity for CNPase or NG2, cell-specific markers for oligodendrocytes and their progenitors, respectively. In the spinal cord from mice with EAE, the expression of protease M/neurosin mRNA in CNPase-positive cells appeared to be increased while double-labeled cells positive for protease M/neurosin mRNA and NG2 were rarely found in areas associated with demyelinating lesions. Although a prominent accumulation of inflammatory cells including T-cells was observed in the vicinity of demyelinated lesions, these cells were not associated with protease M/neurosin mRNA expression. The levels of protease M/neurosin mRNA expression were unchanged in the spleen and even decreased in the thymus during the course of EAE. These observations suggest that the differential expression of protease M/neurosin in mature oligodendrocytes and their progenitors is involved in the pathogenesis of MS and EAE.
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PMID:Differential expression of protease M/neurosin in oligodendrocytes and their progenitors in an animal model of multiple sclerosis. 1591 Nov 26

Human kallikrein-related peptidase 6 (KLK6) is a member of the kallikrein family of serine-type proteases, characterized as an arginine-specific digestive-type protease capable of degrading a wide-variety of extracellular matrix proteins. KLK6 has been proposed to be a useful biomarker for breast and ovarian cancer prognosis, is abundantly expressed in the CNS and cerebrospinal fluid, and is intimately associated with regions of active inflammatory demyelination in multiple sclerosis (MS) lesions. Inhibition of KLK6 results in delayed onset and reduced severity of symptoms associated with experimental autoimmune encephalomyelitis, suggesting a key effector role for this protease in CNS inflammatory disease. KLK6 has been shown to autolytically cleave internally, leading to inactivation and suggesting a negative feedback inhibition control mechanism. Alternatively, the ability of KLK6 to self-activate has also been reported, suggesting a positive feedback activation loop control mechanism. Activation of pro-KLK6 requires hydrolysis after a Lys residue; however, KLK6 exhibits 2 order of magnitude reduced affinity for hydrolysis after Lys versus Arg residues; therefore, the ability to autolytically activate has been called into question. In the present study the catalytic activity of KLK6 toward its pro-sequence and internal autolytic sequence is characterized. The results show that the ability of KLK6 to activate pro-KLK6 is essentially negligible when compared to the rate of the internal autolytic inactivation or to the ability of other proteases to activate pro-KLK6. The results thus show that the primary autolytic regulatory mechanism of KLK6 is negative feedback inhibition, and activation is likely achieved through the action of a separate protease.
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PMID:The autolytic regulation of human kallikrein-related peptidase 6. 1741 74

Recent studies provide a functional link between kallikrein 6 (Klk6) and the development and progression of disease in patients with multiple sclerosis (MS) and in its murine models. To evaluate the involvement of additional kallikrein family members, we compared Klk6 expression with four other kallikreins (Klk1, Klk7, Klk8, and Klk10) in the brain and spinal cord of mice infected with Theiler's murine encephalomyelitis virus, an experimental model of progressive MS. The robust upregulation of Klk6 and Klk8 in the brain during the acute phase of viral encephalitis and in the spinal cord during disease development and progression points to their participation in inflammation, demyelination, and progressive axon degeneration. More limited changes in Klk1, Klk7, and Klk10 were also observed. In addition, Klk1, Klk6, and Klk10 were dynamically regulated in T cells in vitro as a recall response to viral antigen and in activated monocytes, pointing to their activities in the development of adaptive and innate immune function. Together, these results point to overlapping and unique roles for multiple kallikreins in the development and progression of virus-mediated central nervous system inflammatory demyelinating disease, including activities in the development of the adaptive and innate immune response, in demyelination, and in progressive axon degeneration.
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PMID:Differential expression of multiple kallikreins in a viral model of multiple sclerosis points to unique roles in the innate and adaptive immune response. 2515 87