Activity of a newly identified serine protease in CNS demyelination

Scarisbrick, Isobel A.; Blaber, Sachiko I.; Lucchinetti, Claudia F.; Genain, Claude P.; Blaber, Michael; Rodriguez, Moses

doi:10.1093/brain/awf142

Cited by 122 publications

(199 citation statements)

References 64 publications

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“…Thus, with regard to enzymatic activity toward myelin-related and extracellular proteins and autolytic properties, hK6 and rat MSP appear to be true functional homologues. The ability of both rat MSP and hK6 to degrade myelin-associated proteins, coupled with data showing that this enzyme is abundantly expressed within inflammatory cells at sites of demyelination in murine models of multiple sclerosis and associated lesions, supports the idea that this enzyme may play a pivotal role in demyelinating disease (18,26,27,50). Autolytic Activity of hK6 -Determination of the x-ray structure of hK6 provides an opportunity to further characterize the autolytic regulation of MSP/hK6.…”

Section: Human Kallikrein 6 Is Functionally Related To Rat Msp-mentioning

confidence: 75%

“…The biochemical and structural data also support the original hypothesis by Isackson and co-workers (18) that the MSP/KLK6 gene codes for a trypsin-like degradative protease that is expressed in the brain. Since our recent studies implicate excess MSP/hK6 activity in the development of immune mediated demyelination in both animal models of multiple sclerosis and in human multiple sclerosis lesions (27,50), the availability of an atomic model of mature hK6, reported herein, may prove useful in the design of specific and potentially therapeutic inhibitors of this unique enzyme.…”

Section: Human Kallikrein 6 Is Functionally Related To Rat Msp-mentioning

confidence: 93%

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Crystal Structure and Biochemical Characterization of Human Kallikrein 6 Reveals That a Trypsin-like Kallikrein Is Expressed in the Central Nervous System

Bernett

Blaber

Scarisbrick

et al. 2002

Journal of Biological Chemistry

163

173

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The human kallikreins are a large multigene family of closely related serine-type proteases. In this regard, they are similar to the multigene kallikrein families characterized in mice and rats. There is a much more extensive body of knowledge regarding the function of mouse and rat kallikreins in comparison with the human kallikreins. Human kallikrein 6 has been proposed as the homologue to rat myelencephalon-specific protease, an arginine-specific degradative-type protease abundantly expressed in the central nervous system and implicated in demyelinating disease. We present the xray crystal structure of mature, active recombinant human kallikrein 6 at 1.75-Å resolution. This high resolution model provides the first three-dimensional view of one of the human kallikreins and one of only a few structures of serine proteases predominantly expressed in the central nervous system. Enzymatic data are presented that support the identification of human kallikrein 6 as the functional homologue of rat myelencephalon-specific protease and are corroborated by a molecular phylogenetic analysis. Furthermore, the xray data provide support for the characterization of human kallikrein 6 as a degradative protease with structural features more similar to trypsin than the regulatory kallikreins.Recent studies demonstrate that humans have a large multigene family of at least 15 different kallikreins (serine type proteases, abbreviated as KLK 1 in reference to the gene, or hK in reference to the protein) (1). Similarly, the mouse and rat kallikrein gene families are characterized by a large number of closely related members that presumably arose because of gene duplication events (2-6). The different members of the mouse and rat kallikreins are characterized by a high degree of amino acid identity, but typically exhibit different preferences toward peptide substrates (7-12). Several human kallikreins have been identified as potentially useful diagnostic markers for breast (KLK3 and KLK6), prostate (KLK2 and KLK3), and ovarian (KLK6, KLK9, KLK10, and KLK11) cancers as well as neurodegenerative diseases such as Alzheimer's (KLK6) (1, 13-17).Myelencephalon-specific protease (MSP) is a member of the rat kallikrein gene family that is abundantly expressed in the rodent central nervous system and shown to be up-regulated in response to glutamate receptor-mediated excitotoxic injury (18). Potential human homologues to rat MSP have also been identified (18) and have been alternatively named protease M (19), Zyme (20), and neurosin (21). Mouse homologues to MSP have been reported as brain and skin serine protease (BSSP) (22) and brain serine protease (BSP) (23). It has been postulated that MSP/protease M/neurosin may play a key role in the regulation of myelin turnover and in demyelinating disease (18, 24 -27), including the development of multiple sclerosis lesions (25). Furthermore, this kallikrein may also play a role in the degradation of ␤-amyloid or turnover of amyloid precursor protein (28,29). The kinetic properties of MSP have ident...

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Section: Human Kallikrein 6 Is Functionally Related To Rat Msp-mentioning

confidence: 75%

Section: Human Kallikrein 6 Is Functionally Related To Rat Msp-mentioning

confidence: 93%

Crystal Structure and Biochemical Characterization of Human Kallikrein 6 Reveals That a Trypsin-like Kallikrein Is Expressed in the Central Nervous System

Bernett

Blaber

Scarisbrick

et al. 2002

Journal of Biological Chemistry

163

173

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“…It has been suggested that oligodendrocytes and myelin have endogenous protease activity with the potential to degrade myelin proteins (Sato et al, 1982;Berlet et al, 1984;Chantry et al, 1989;Scarisbrick et al, 2002;Terayama et al, 2005b). The in vitro biochemical assay showed that neuropsin is capable of degrading MBP (He et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Neuropsin promotes oligodendrocyte death, demyelination and axonal degeneration after spinal cord injury

et al. 2007

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Abbreviations: SCI, spinal cord injury; DIG, digoxigenin; APC, adenomatus polyposis coli; MBP, myelin basic protein; TUNEL, TdT-mediated dUTP-fluorescein nick end labeling -3 - AbstractPrevious studies indicated that the expression of neuropsin, a serine protease, is induced in mature oligodendrocytes after injury to the central nervous system (CNS). The pathophysiology of spinal cord injury (SCI) involves primary and secondary mechanisms, the latter contributing further to permanent losses of function. To explore the role of neuropsin after SCI, histochemical and behavioral analyses were performed in wild-type (WT) and neuropsin-deficient (neuropsin -/-) mice using a crush injury model, a well-characterized and consistently reproducible model of SCI. In situ hybridization revealed that neuropsin mRNA expression was induced in the spinal cord white matter from WT mice after crush SCI, peaking at day 4. Neuropsin -/-mice showed attenuated demyelination, oligodendrocyte death, and axonal damage after SCI.Although axonal degeneration in the corticospinal tract was obvious caudal to the lesion site in both strains of mice after SCI, the number of surviving nerve fibers caudal to the lesion was significantly larger in neuropsin -/-mice than WT mice. Behavioral analysis revealed that the recovery at days 10-42 was significantly improved in neuropsin -/-mice compared to WT mice in spite of the severe initial hindlimb impairments due to SCI in both strains. These observations suggest that neuropsin is involved in the secondary phase of the pathogenesis of SCI mediated by demyelination, oligodendrocyte death, and axonal degeneration.-4 -

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“…Our recent study has demonstrated that traumatic injury to the spinal cord causes changes in the expression of protease M/neurosin in oligodendrocytes and their progenitors [20]. Scarisbrick et al [5,16,17] Then adjusted pH to 7.3 with 1 M Tris-HCl, pH 7.5.…”

Section: Introductionmentioning

confidence: 99%

Differential expression of protease M/neurosin in oligodendrocytes and their progenitors in an animal model of multiple sclerosis

Terayama

Bandô

Jiang³

et al. 2005

Neuroscience Letters

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Elsevier, Terayama, Ryuji ; Bando, Yoshio ; Jiang, Ying-Ping ; Mitrovic, Branka ; Yoshida, Shigetaka, Neuroscience Letters, 382(1-2), 2005, 82-87. authorTo 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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Activity of a newly identified serine protease in CNS demyelination

Cited by 122 publications

References 64 publications

Crystal Structure and Biochemical Characterization of Human Kallikrein 6 Reveals That a Trypsin-like Kallikrein Is Expressed in the Central Nervous System

Crystal Structure and Biochemical Characterization of Human Kallikrein 6 Reveals That a Trypsin-like Kallikrein Is Expressed in the Central Nervous System

Neuropsin promotes oligodendrocyte death, demyelination and axonal degeneration after spinal cord injury

Differential expression of protease M/neurosin in oligodendrocytes and their progenitors in an animal model of multiple sclerosis

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