Neuroserpin: a selective inhibitor of tissue-type plasminogen activator in the central nervous system

Abstract

SummaryNeuroserpin 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.

Progesterone and its Metabolite Allopregnanolone Differentially Regulate Hemostatic Proteins after Traumatic Brain Injury

“…It has been shown to be neuroprotective in several animal models of stroke (Yepes and Lawrence, 2004). Our findings show that neuroserpin is increased by both PROG and ALLO treatment.…”

Genomic abnormalities of the murine model of Fabry disease after disease-related perturbation, a systems biology approach

“…The up-regulation of Sod3 following ERT is likely an adaptive response to restoring vascular health in the Fabry aorta. Other genes present in the Sod3 subgraph are Cbfa2t3h, a transcription factor (22); Dhx15, which forms part of a putative family of RNA helicases (23); Fbxo33, which forms part of the F-box protein family components of modular E3 ubiquitin protein ligases (24); Asah1, which is the gene for acid ceramidase, the enzyme that is deficient in Farber Disease (25); and Serpinf1 (␣-2-antiplasmin), which is part of the serine protease inhibitor family that has broad functions, including antiangiogenesis, but is also known to decrease the activity of free plasmin (26) while at a cellular level (e.g., in the brain) it is known to be neuroprotective (27). We recently found a generalized perturbation of ␣-2-antiplasmin and plasminogen in children with Fabry disease by using a similar disease-related perturbation (28).…”

Neuroserpin Protects Neurons from Ischemia-Induced Plasmin-Mediated Cell Death Independently of Tissue-Type Plasminogen Activator Inhibition

“…Biochemical studies have led to the hypothesis that neuroserpin is the selective inhibitor of tPA in the CNS, 31 and that neuroserpin's neuroprotective role is mediated by its ability to inhibit tPA activity. However, the observation that neuroserpin-deficient mice not only have unchanged tPA activity but also exhibit significant abnormalities in the regulation of emotional behavior, 32 and that neuroserpin regulates cell adhesion independently of its activity as inhibitor of tPA activity, 33 indicates the existence of tPA-independent effects for neuroserpin.…”