Modulations of the neuronal trafficking of tissue-type plasminogen activator (tPA) influences glutamate release.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
18 01 2023
18 01 2023
Historique:
received:
01
11
2022
accepted:
22
12
2022
revised:
15
12
2022
entrez:
17
1
2023
pubmed:
18
1
2023
medline:
20
1
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36650132
doi: 10.1038/s41419-022-05543-9
pii: 10.1038/s41419-022-05543-9
pmc: PMC9845363
doi:
Substances chimiques
Tissue Plasminogen Activator
EC 3.4.21.68
Glutamic Acid
3KX376GY7L
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
34Informations de copyright
© 2023. The Author(s).
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