Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the Neuroserpin gene have been reported to cause familial presenile dementia. We describe a new family in which the S52R Neuroserpin mutation is associated with progressive myoclonus epilepsy in 2 siblings. The proband presented myoclonus and epilepsy at age 24, his brother and mother presented a similar disorder when they were 25. A clinical diagnosis of progressive myoclonus epilepsy was made on the proband and his brother. Skin and liver biopsies did not reveal the presence of cytological alterations in the proband. His neurological status worsened over the subsequent 19 yr during which he became demented and had uncontrollable seizures. He died at 43 yr of age from aspiration pneumonia. Neuropathologically, eosinophilic bodies, which were positive for periodic acid-Schiff and immunoreactive with antibodies against human neuroserpin, were present in the perikarya and cell processes of the neurons. They were found in large numbers in the cerebral cortex and substantia nigra and to a lesser extent, in most subcortical gray areas, spinal cord, and dorsal root ganglia. By electron microscopy, the intracytoplasmic bodies were contained within the membranes of the rough endoplasmic reticulum. Occasionally neuroserpin immunopositivity was seen throughout the cytoplasm, even without the presence of well-defined bodies. Our study characterizes for the first time the neuropathologic phenotype associated with hereditary progressive myoclonus epilepsy caused by the S52R Neuroserpin mutation.
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PMID:Neuroserpin mutation S52R causes neuroserpin accumulation in neurons and is associated with progressive myoclonus epilepsy. 1113 27

Neuroserpin is a member of the serine proteinase inhibitor (serpin) gene family that reacts preferentially with tissue-type plasminogen activator (tPA) and is primarily localized to neurons in regions of the brain where tPA is also found. Outside of the central nervous system (CNS) tPA is predominantly found in the blood where its primary function is as a thrombolytic enzyme. However, tPA is also expressed within the CNS where it has a very different function, promoting events associated not only with synaptic plasticity but also with cell death in a number of settings, such as cerebral ischemia and seizures. Neuroserpin is released from neurons in response to neuronal depolarization and plays an important role in the development of synaptic plasticity. Following the onset of cerebral ischemia there is an increase in both tPA activity and neuroserpin expression in the area surrounding the necrotic core (ischemic penumbra), and treatment with neuroserpin following ischemic stroke or overexpression of the neuroserpin gene results in a significant decrease in the volume of the ischemic area as well as in the number of apoptotic cells. TPA activity and neuroserpin expression are also increased in specific areas of the brain by seizures, and treatment with neuroserpin slows the progression of seizure activity throughout the CNS and results in significant neuronal survival in the hippocampus. Mutations in human neuroserpin result in a form of autosomal dominant inherited dementia which is characterized by the presence of intraneuronal inclusion bodies and is known as Familial Encephalopathy with Neuroserpin Inclusion Bodies.
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PMID:Neuroserpin: a selective inhibitor of tissue-type plasminogen activator in the central nervous system. 1498 20

Tissue-type plasmingen activator (tPA) is a highly specific serine proteinase that activates the zymogen plasminogen to the broad-specificity proteinase plasmin. tPA is found in the blood, where its primary function is as a thrombolytic enzyme, as well as in the central nervous system (CNS), where it promotes events associated with synaptic plasticity and cell death in a number of settings, such as cerebral ischemia and seizures. Neuroserpin is a fully inhibitory serine proteinase inhibitor (serpin) that reacts preferentially with tPA, and is located in regions of the brain where either tPA message or tPA protein are also found, suggesting that neuroserpin is the selective inhibitor of tPA in the CNS. There is a growing body of evidence demonstrating the participation of tPA in a number of physiologic and pathologic events in the CNS, and the role of neuroserpin as the natural regulator of tPA's activity in these processes.
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PMID:Tissue-type plasminogen activator and neuroserpin: a well-balanced act in the nervous system? 1526 88

Tissue-type plasminogen activator (tPA) is a highly specific serine proteinase that activates the zymogen plasminogen to the broad-specificity proteinase plasmin. Tissue-type plasminogen activator is found not only in the blood, where its primary function is as a thrombolytic enzyme, but also in the central nervous system (CNS), where it promotes events associated with synaptic plasticity and acts as a regulator of the permeability of the neurovascular unit. Tissue-type plasminogen activator has also been associated with pathological events in the CNS such as cerebral ischemia and seizures. Neuroserpin is an inhibitory serpin that reacts preferentially with tPA and is located in regions of the brain where either tPA message or tPA protein are also found, indicating that neuroserpin is the selective inhibitor of tPA in the CNS. There is a growing body of evidence demonstrating the participation of tPA in a number of physiological and pathological events in the CNS, as well as the role of neuroserpin as the natural regulator of tPA's activity in these processes. This review will focus on nonhemostatic roles of tPA in the CNS with emphasis on its newly described function as a regulator of permeability of the neurovascular unit and on the regulatory role of neuroserpin in these events.
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PMID:New functions for an old enzyme: nonhemostatic roles for tissue-type plasminogen activator in the central nervous system. 1556 35

Neuroserpin is a member of the serpin family of serine protease inhibitors. Tissue distribution analysis reveals a predominantly neuronal expression during the late stages of neurogenesis and, in the adult brain, in areas where synaptic changes are associated with learning and memory (synaptic plasticity). In vitro studies revealed complex formation between neuroserpin and different serine proteases, i.e. tPA, uPA, and plasmin. The neuroserpin-target complex has so far not been characterized in vivo. However, some investigations help to understand the functional role of this serpin. Neuroserpin was shown to be involved in the regulation of the morphology of neuroendocrine cells in culture, possibly by modulating the degradation of the extracellular matrix by proteolytic enzymes such as tPA. Moreover, a role of neuroserpin in mood regulation has been deduced from the over- and underexpression of neuroserpin in genetically modified mice, which showed increased anxiety and novelty-induced hypo-locomotion. In pathological conditions of the central nervous system (i.e. stroke and seizures), neuroserpin plays a neuroprotective role, probably by blocking the deleterious effects of tPA. A familial form of a neurodegenerative disease, termed familial encephalopathy with neuroserpin inclusion bodies, is caused by point mutations in the neuroserpin gene. This condition is characterized by the intracellular polymerization and accumulation of mutated neuroserpin, leading to neuronal death and dementia.
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PMID:Neuroserpin. 1614 12

Various studies suggest that proteolytic activity may be involved in a number of neurodegenerative disorders, including stroke and seizure. In this report, we examined the role of tryptic serine proteases, plasminogen activators (PAs), in the evolution of a neurodegenerative disease. Transgenic mice overexpressing an axonally secreted inhibitor of serine proteases (neuroserpin) were crossed with mice characterized by a "dying-back" motor neuron disease [progressive motor neuronopathy (pmn/pmn)]. Compared with pmn/pmn mice that showed an increase in PA activity, double mutant mice had decreased PA activity in sciatic nerves and spinal cord; their lifespan was increased by 50%, their motor behavior was stabilized, and histological analysis revealed increased numbers of myelinated axons and rescue of motoneuron number and size. This is the first report showing that a class of serine proteases (PAs) may be involved in the pathogenesis of a motor neuron disease and more specifically in axonal degeneration. Inhibiting serine proteases could offer a new strategy for delaying these disorders.
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PMID:An inhibitor of serine proteases, neuroserpin, acts as a neuroprotective agent in a mouse model of neurodegenerative disease. 1703 47

Tissue-type plasminogen activator (t-PA), initially characterized for its critical role in fibrinolysis, also has key functions in both physiologic and pathologic processes in the CNS. Neuroserpin (NSP) is a t-PA specific serine protease inhibitor (serpin) found almost exclusively in the CNS that regulates t-PA's proteolytic activity and protects against t-PA mediated seizure propagation and blood-brain barrier disruption. This report demonstrates that NSP inhibition of t-PA varies profoundly as a function of pH within the biologically relevant pH range for the CNS, and reflects the stability, rather than the formation of NSP: t-PA acyl-enzyme complexes. Moreover, NSP differentiates between the zymogen-like single chain form (single chain t-PA, sct-PA) and the mature protease form (two chain t-PA, tct-PA) of t-PA, demonstrating different pH profiles for protease inhibition, different pH ranges over which catalytic deacylation occurs, and different pH dependent profiles of deacylation rates for each form of t-PA. NSP's pH dependent inhibition of t-PA is not accounted for by differential acylation, and is specific for the NSP-t-PA serpin-protease pair. These results demonstrate a novel mechanism for the differential regulation of the two forms of t-PA in the CNS, and suggest a potential specific regulatory role for CNS pH in controlling t-PA proteolytic activity.
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PMID:Neuroserpin Differentiates Between Forms of Tissue Type Plasminogen Activator via pH Dependent Deacylation. 2737 51