Tissue plasminogen activator as a key effector in neurobiology and neuropathology

Teesalu, Tambet; Kulla, Andres; Asser, Toomas; Koskiniemi, M.; Vaheri, Antti

doi:10.1042/bst0300183

Cited by 45 publications

(15 citation statements)

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“…Late in the course of the disease, additional numbers of microglia may be activated in response to degeneration of neurons, producing even more neurotoxic factors. The accumulation of high numbers of activated microglia may further be responsible for the high level of tPA, which has been shown to be associated with neuronal degeneration (2,42,43), and this may result in progressively advanced neurological disease in a short period of time.…”

Section: Discussionmentioning

confidence: 99%

Neurodegeneration Induced by PVC-211 Murine Leukemia Virus Is Associated with Increased Levels of Vascular Endothelial Growth Factor and Macrophage Inflammatory Protein 1α and Is Inhibited by Blocking Activation of Microglia

Hanson

Cmarik

et al. 2009

J Virol

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PVC-211 murine leukemia virus (MuLV) is a neuropathogenic retrovirus that has undergone genetic changes from its nonneuropathogenic parent, Friend MuLV, that allow it to efficiently infect rat brain capillary endothelial cells (BCEC). To clarify the mechanism by which PVC-211 MuLV expression in BCEC induces neurological disease, we examined virus-infected rats at various times during neurological disease progression for vascular and inflammatory changes. As early as 2 weeks after virus infection and before any marked appearance of spongiform neurodegeneration, we detected vessel leakage and an increase in size and number of vessels in the areas of the brain that eventually become diseased. Consistent with these findings, the amount of vascular endothelial growth factor (VEGF) increased in the brain as early as 1 to 2 weeks postinfection. Also detected at this early disease stage was an increased level of macrophage inflammatory protein 1␣ (MIP-1␣), a cytokine involved in recruitment of microglia to the brain. This was followed at 3 weeks postinfection by a marked accumulation of activated microglia in the spongiform areas of the brain accompanied by an increase in tissue plasminogen activator, a product of microglia implicated in neurodegeneration. Pathological observations at the end stage of the disease included loss of neurons, decreased myelination, and mild muscle atrophy. Treatment of PVC-211 MuLV-infected rats with clodronate-containing liposomes, which specifically kill microglia, significantly blocked neurodegeneration. Together, these results suggest that PVC-211 MuLV infection of BCEC results in the production of VEGF and MIP-1␣, leading to the vascular changes and microglial activation necessary to cause neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Neurodegeneration Induced by PVC-211 Murine Leukemia Virus Is Associated with Increased Levels of Vascular Endothelial Growth Factor and Macrophage Inflammatory Protein 1α and Is Inhibited by Blocking Activation of Microglia

Hanson

Cmarik

et al. 2009

J Virol

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“…The tPAgene tPAisproduced by different cell types, in particular by endothelialcells, keratinocytes, osteoblasts and osteoclasts, melanocytes and neurons (60)(61)(62). Of neoplastic cells, tPAmay be produced by melanoma,neuroblastoma,ovarian cancer,breast cancer and pancreaticc ancer cells (63)(64)(65).…”

Section: Regulation Of Gene Transcriptionmentioning

confidence: 99%

Transcriptional and posttranscriptional regulation of the plasminogen activator system

Nagamine¹,

Medcalf²,

Muñoz‐Cánoves³

2005

Thromb Haemost

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SummaryThecoreprotein components of the plasminogenactivator (PA) system aret wo plasminogen activators, twop lasminogen activator inhibitorsand aurokinasetype plasminogenactivator-specific cell surfacer eceptor.Varioustypesofbiologicalr egulation areexerted through the interplayofthese components mutually and with extracellular matrix proteins and cell membrane proteins, with or without involving proteolytic activity.Reflecting these diverse biologicalroles, thelevel and activityofeach componento ft he PA system is under the control of av ariety of Keywords Review, plasminogen activator,generegulation,mRNA stability regulatorym echanisms. Thee xpression levelo fap rotein reflects the levelofthe corresponding mRNA, which is essentially the netresult of de novo synthesis,i.e.transcription, and degradation. Manyr ecents tudiesh aves hown thatt he regulation of mRNA stabilityisdynamic and cell specific.Accordingly, we are learning that the mRNAsofthe PA system arealsothe subject of diverse regulatorymechanisms. In this shortreview, we summarize current understanding of the transcriptionaland mRNAstabilityregulationofthe PA system.

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“…The serine protease tissue plasminogen activator (tPA) is released by both neurons and glia in the brain (Teesalu et al, 2001;Tsirka, 2001). tPA expression can be found in many brain regions, including the hippocampus, amygdala, and cerebellum, where it plays a role in experience-driven synaptic plasticity (Baranes et al, 1998;Pawlak et al, 2003;Seeds et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Rapid, Activity-Induced Increase in Tissue Plasminogen Activator Is Mediated by Metabotropic Glutamate Receptor-Dependent mRNA Translation

Shin¹,

Kundel²,

Wells³

2004

J. Neurosci.

128

116

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Long-term synaptic plasticity is both protein synthesis-dependent and synapse-specific. Therefore, the identity of the newly synthesized proteins, their localization, and mechanism of regulation are critical to our understanding of this process. Tissue plasminogen activator (tPA) is a secreted protease required for some forms of long-term synaptic plasticity. Here, we show tPA activity is rapidly increased in hippocampal neurons after glutamate stimulation. This increase in tPA activity corresponds to an increase in tPA protein synthesis that results from the translational activation of mRNA present at the time of stimulation. Furthermore, the mRNA encoding tPA is present in dendrites and is rapidly polyadenylated after glutamate stimulation. Both the polyadenylation of tPA mRNA and the subsequent increase in tPA protein is dependent on metabotropic glutamate receptor (mGluR) activation. A similar mGluR-dependent increase in tPA activity was detected after stimulation of a synaptic fraction isolated from the hippocampus, suggesting tPA synthesis is occurring in the synaptodendritic region. Finally, we demonstrate that tPA mRNA is bound by the mRNA-binding protein CPEB (cytoplasmic polyadenylation element binding protein-1), a protein known to regulate mRNA translation via polyadenylation. These results indicate that neurons are capable of synthesizing a secreted protein in the synaptic region, that mGluR activation induces mRNA polyadenylation and translation of specific mRNA, and suggest a model for synaptic plasticity whereby translational regulation of an immediate early gene precedes the increase in gene transcription.

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Tissue plasminogen activator as a key effector in neurobiology and neuropathology

Cited by 45 publications

References 0 publications

Neurodegeneration Induced by PVC-211 Murine Leukemia Virus Is Associated with Increased Levels of Vascular Endothelial Growth Factor and Macrophage Inflammatory Protein 1α and Is Inhibited by Blocking Activation of Microglia

Neurodegeneration Induced by PVC-211 Murine Leukemia Virus Is Associated with Increased Levels of Vascular Endothelial Growth Factor and Macrophage Inflammatory Protein 1α and Is Inhibited by Blocking Activation of Microglia

Transcriptional and posttranscriptional regulation of the plasminogen activator system

Rapid, Activity-Induced Increase in Tissue Plasminogen Activator Is Mediated by Metabotropic Glutamate Receptor-Dependent mRNA Translation

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