Modulations of the neuronal trafficking of tissue-type plasminogen activator (tPA) influences glutamate release
Abstract The discovery of the neuronal expression of the serine protease tissue-type plasminogen activator (tPA) has opened new avenues of research, with important implications in the physiopathology of the central nervous system. For example, the interaction of tPA with synaptic receptors (NMDAR, L...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-01-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05543-9 |
| _version_ | 1797945694548393984 |
|---|---|
| author | Alexandre Varangot Simon Lebatard Mathys Bellemain-Sagnard Laurent Lebouvier Yannick Hommet Denis Vivien |
| author_facet | Alexandre Varangot Simon Lebatard Mathys Bellemain-Sagnard Laurent Lebouvier Yannick Hommet Denis Vivien |
| author_sort | Alexandre Varangot |
| collection | DOAJ |
| description | Abstract The discovery of the neuronal expression of the serine protease tissue-type plasminogen activator (tPA) has opened new avenues of research, with important implications in the physiopathology of the central nervous system. For example, the interaction of tPA with synaptic receptors (NMDAR, LRP1, Annexin II, and EGFR) and its role in the maturation of BDNF have been reported to influence synaptic plasticity and neuronal survival. However, the mechanisms regulating the neuronal trafficking of tPA are unknown. Here, using high-resolution live cell imaging and a panel of innovative genetic approaches, we first unmasked the dynamic characteristics of the dendritic and axonal trafficking of tPA-containing vesicles under different paradigms of neuronal activation or inhibition. We then report a constitutive exocytosis of tPA- and VAMP2-positive vesicles, dramatically increased in conditions of neuronal activation, with a pattern which was mainly dendritic and thus post-synaptic. We also observed that the synaptic release of tPA led to an increase of the exocytosis of VGlut1 positive vesicles containing glutamate. Finally, we described alterations of the trafficking and exocytosis of neuronal tPA in cultured cortical neurons prepared from tau-22 transgenic mice (a preclinical model of Alzheimer’s disease (AD)). Altogether, these data provide new insights about the neuronal trafficking of tPA, contributing to a better knowledge of the tPA-dependent brain functions and dysfunctions. |
| first_indexed | 2024-04-10T20:59:09Z |
| format | Article |
| id | doaj.art-baaf6f26c5d6419ab97390e0b7857084 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-10T20:59:09Z |
| publishDate | 2023-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-baaf6f26c5d6419ab97390e0b78570842023-01-22T12:26:42ZengNature Publishing GroupCell Death and Disease2041-48892023-01-0114111510.1038/s41419-022-05543-9Modulations of the neuronal trafficking of tissue-type plasminogen activator (tPA) influences glutamate releaseAlexandre Varangot0Simon Lebatard1Mathys Bellemain-Sagnard2Laurent Lebouvier3Yannick Hommet4Denis Vivien5Normandie Univ, UNICAEN, INSERM U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Cyceron, Institut Blood and Brain @ Caen-Normandie (BB@C)Normandie Univ, UNICAEN, INSERM U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Cyceron, Institut Blood and Brain @ Caen-Normandie (BB@C)Normandie Univ, UNICAEN, INSERM U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Cyceron, Institut Blood and Brain @ Caen-Normandie (BB@C)Normandie Univ, UNICAEN, INSERM U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Cyceron, Institut Blood and Brain @ Caen-Normandie (BB@C)Normandie Univ, UNICAEN, INSERM U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Cyceron, Institut Blood and Brain @ Caen-Normandie (BB@C)Normandie Univ, UNICAEN, INSERM U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Cyceron, Institut Blood and Brain @ Caen-Normandie (BB@C)Abstract The discovery of the neuronal expression of the serine protease tissue-type plasminogen activator (tPA) has opened new avenues of research, with important implications in the physiopathology of the central nervous system. For example, the interaction of tPA with synaptic receptors (NMDAR, LRP1, Annexin II, and EGFR) and its role in the maturation of BDNF have been reported to influence synaptic plasticity and neuronal survival. However, the mechanisms regulating the neuronal trafficking of tPA are unknown. Here, using high-resolution live cell imaging and a panel of innovative genetic approaches, we first unmasked the dynamic characteristics of the dendritic and axonal trafficking of tPA-containing vesicles under different paradigms of neuronal activation or inhibition. We then report a constitutive exocytosis of tPA- and VAMP2-positive vesicles, dramatically increased in conditions of neuronal activation, with a pattern which was mainly dendritic and thus post-synaptic. We also observed that the synaptic release of tPA led to an increase of the exocytosis of VGlut1 positive vesicles containing glutamate. Finally, we described alterations of the trafficking and exocytosis of neuronal tPA in cultured cortical neurons prepared from tau-22 transgenic mice (a preclinical model of Alzheimer’s disease (AD)). Altogether, these data provide new insights about the neuronal trafficking of tPA, contributing to a better knowledge of the tPA-dependent brain functions and dysfunctions.https://doi.org/10.1038/s41419-022-05543-9 |
| spellingShingle | Alexandre Varangot Simon Lebatard Mathys Bellemain-Sagnard Laurent Lebouvier Yannick Hommet Denis Vivien Modulations of the neuronal trafficking of tissue-type plasminogen activator (tPA) influences glutamate release Cell Death and Disease |
| title | Modulations of the neuronal trafficking of tissue-type plasminogen activator (tPA) influences glutamate release |
| title_full | Modulations of the neuronal trafficking of tissue-type plasminogen activator (tPA) influences glutamate release |
| title_fullStr | Modulations of the neuronal trafficking of tissue-type plasminogen activator (tPA) influences glutamate release |
| title_full_unstemmed | Modulations of the neuronal trafficking of tissue-type plasminogen activator (tPA) influences glutamate release |
| title_short | Modulations of the neuronal trafficking of tissue-type plasminogen activator (tPA) influences glutamate release |
| title_sort | modulations of the neuronal trafficking of tissue type plasminogen activator tpa influences glutamate release |
| url | https://doi.org/10.1038/s41419-022-05543-9 |
| work_keys_str_mv | AT alexandrevarangot modulationsoftheneuronaltraffickingoftissuetypeplasminogenactivatortpainfluencesglutamaterelease AT simonlebatard modulationsoftheneuronaltraffickingoftissuetypeplasminogenactivatortpainfluencesglutamaterelease AT mathysbellemainsagnard modulationsoftheneuronaltraffickingoftissuetypeplasminogenactivatortpainfluencesglutamaterelease AT laurentlebouvier modulationsoftheneuronaltraffickingoftissuetypeplasminogenactivatortpainfluencesglutamaterelease AT yannickhommet modulationsoftheneuronaltraffickingoftissuetypeplasminogenactivatortpainfluencesglutamaterelease AT denisvivien modulationsoftheneuronaltraffickingoftissuetypeplasminogenactivatortpainfluencesglutamaterelease |