The interaction of tPA with NMDAR1 drives neuroinflammation and neurodegeneration in α-synuclein-mediated neurotoxicity
Abstract The thrombolytic protease tissue plasminogen activator (tPA) is expressed in the CNS, where it regulates diverse functions including neuronal plasticity, neuroinflammation, and blood-brain-barrier integrity. However, its role in different brain regions such as the substantia nigra (SN) is l...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-01-01
|
| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-025-03336-3 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832594534580617216 |
|---|---|
| author | Daniel Torrente Enming J. Su Alí Francisco Citalán-Madrid Gerald P. Schielke Daniel Magaoay Mark Warnock Tamara Stevenson Kris Mann Flavie Lesept Nathalie Delétage Manuel Blanc Erin H. Norris Denis Vivien Daniel A. Lawrence |
| author_facet | Daniel Torrente Enming J. Su Alí Francisco Citalán-Madrid Gerald P. Schielke Daniel Magaoay Mark Warnock Tamara Stevenson Kris Mann Flavie Lesept Nathalie Delétage Manuel Blanc Erin H. Norris Denis Vivien Daniel A. Lawrence |
| author_sort | Daniel Torrente |
| collection | DOAJ |
| description | Abstract The thrombolytic protease tissue plasminogen activator (tPA) is expressed in the CNS, where it regulates diverse functions including neuronal plasticity, neuroinflammation, and blood-brain-barrier integrity. However, its role in different brain regions such as the substantia nigra (SN) is largely unexplored. In this study, we characterize tPA expression, activity, and localization in the SN using a combination of retrograde tracing and β-galactosidase tPA reporter mice. We further investigate tPA’s potential role in SN pathology in an α-synuclein mouse model of Parkinson’s disease (PD). To characterize the mechanism of tPA action in α-synuclein-mediated pathology in the SN and to identify possible therapeutic pathways, we performed RNA-seq analysis of the SN and used multiple transgenic mouse models. These included tPA deficient mice and two newly developed transgenic mice, a knock-in model expressing endogenous levels of proteolytically inactive tPA (tPA Ala-KI) and a second model overexpressing proteolytically inactive tPA (tPA Ala-BAC). Our findings show that striatal GABAergic neurons send tPA+ projections to dopaminergic (DA)-neurons in the SN and that tPA is released from SN-derived synaptosomes upon stimulation. We also found that tPA levels in the SN increased following α-synuclein overexpression. Importantly, tPA deficiency protects DA-neurons from degeneration, prevents behavioral deficits, and reduces microglia activation and T-cell infiltration induced by α-synuclein overexpression. RNA-seq analysis indicates that tPA in the SN is required for the upregulation of genes involved in the innate and adaptive immune responses induced by α-synuclein overexpression. Overexpression of α-synuclein in tPA Ala-KI mice, expressing only proteolytically inactive tPA, confirms that tPA-mediated neuroinflammation and neurodegeneration is independent of its proteolytic activity. Moreover, overexpression of proteolytically inactive tPA in tPA Ala-BAC mice leads to increased neuroinflammation and neurodegeneration compared to mice expressing normal levels of tPA, suggesting a tPA dose response. Finally, treatment of mice with glunomab, a neutralizing antibody that selectively blocks tPA binding to the N-methyl-D-aspartate receptor-1 (NMDAR1) without affecting NMDAR1 ion channel function, identifies the tPA interaction with NMDAR1 as necessary for tPA-mediated neuroinflammation and neurodegeneration in response to α-synuclein-mediated neurotoxicity. Thus, our data identifies a novel pathway that promotes DA-neuron degeneration and suggests a potential therapeutic intervention for PD targeting the tPA-NMDAR1 interaction. |
| format | Article |
| id | doaj-art-23d700852d0e4e08bfa5a439c1a2cba3 |
| institution | Kabale University |
| issn | 1742-2094 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj-art-23d700852d0e4e08bfa5a439c1a2cba32025-01-19T12:33:26ZengBMCJournal of Neuroinflammation1742-20942025-01-0122112310.1186/s12974-025-03336-3The interaction of tPA with NMDAR1 drives neuroinflammation and neurodegeneration in α-synuclein-mediated neurotoxicityDaniel Torrente0Enming J. Su1Alí Francisco Citalán-Madrid2Gerald P. Schielke3Daniel Magaoay4Mark Warnock5Tamara Stevenson6Kris Mann7Flavie Lesept8Nathalie Delétage9Manuel Blanc10Erin H. Norris11Denis Vivien12Daniel A. Lawrence13Department of Molecular and Integrative Physiology, University of Michigan Medical SchoolDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical SchoolDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical SchoolDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical SchoolDepartment of Molecular and Integrative Physiology, University of Michigan Medical SchoolDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical SchoolDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical SchoolDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical SchoolLys TherapeuticsLys TherapeuticsLys TherapeuticsPatricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller UniversityPhysiopathology and Imaging of Neurological Disorders (PhIND), UNICAEN, INSERM, GIP Cyceron, Institut Blood and Brain @Caen-Normandie (BB@C), UMR-S U1237, Normandie UnivDepartment of Molecular and Integrative Physiology, University of Michigan Medical SchoolAbstract The thrombolytic protease tissue plasminogen activator (tPA) is expressed in the CNS, where it regulates diverse functions including neuronal plasticity, neuroinflammation, and blood-brain-barrier integrity. However, its role in different brain regions such as the substantia nigra (SN) is largely unexplored. In this study, we characterize tPA expression, activity, and localization in the SN using a combination of retrograde tracing and β-galactosidase tPA reporter mice. We further investigate tPA’s potential role in SN pathology in an α-synuclein mouse model of Parkinson’s disease (PD). To characterize the mechanism of tPA action in α-synuclein-mediated pathology in the SN and to identify possible therapeutic pathways, we performed RNA-seq analysis of the SN and used multiple transgenic mouse models. These included tPA deficient mice and two newly developed transgenic mice, a knock-in model expressing endogenous levels of proteolytically inactive tPA (tPA Ala-KI) and a second model overexpressing proteolytically inactive tPA (tPA Ala-BAC). Our findings show that striatal GABAergic neurons send tPA+ projections to dopaminergic (DA)-neurons in the SN and that tPA is released from SN-derived synaptosomes upon stimulation. We also found that tPA levels in the SN increased following α-synuclein overexpression. Importantly, tPA deficiency protects DA-neurons from degeneration, prevents behavioral deficits, and reduces microglia activation and T-cell infiltration induced by α-synuclein overexpression. RNA-seq analysis indicates that tPA in the SN is required for the upregulation of genes involved in the innate and adaptive immune responses induced by α-synuclein overexpression. Overexpression of α-synuclein in tPA Ala-KI mice, expressing only proteolytically inactive tPA, confirms that tPA-mediated neuroinflammation and neurodegeneration is independent of its proteolytic activity. Moreover, overexpression of proteolytically inactive tPA in tPA Ala-BAC mice leads to increased neuroinflammation and neurodegeneration compared to mice expressing normal levels of tPA, suggesting a tPA dose response. Finally, treatment of mice with glunomab, a neutralizing antibody that selectively blocks tPA binding to the N-methyl-D-aspartate receptor-1 (NMDAR1) without affecting NMDAR1 ion channel function, identifies the tPA interaction with NMDAR1 as necessary for tPA-mediated neuroinflammation and neurodegeneration in response to α-synuclein-mediated neurotoxicity. Thus, our data identifies a novel pathway that promotes DA-neuron degeneration and suggests a potential therapeutic intervention for PD targeting the tPA-NMDAR1 interaction.https://doi.org/10.1186/s12974-025-03336-3tPAα-synucleinSubstantia nigraParkinson’s diseaseNeuroinflammationDopaminergic neurons |
| spellingShingle | Daniel Torrente Enming J. Su Alí Francisco Citalán-Madrid Gerald P. Schielke Daniel Magaoay Mark Warnock Tamara Stevenson Kris Mann Flavie Lesept Nathalie Delétage Manuel Blanc Erin H. Norris Denis Vivien Daniel A. Lawrence The interaction of tPA with NMDAR1 drives neuroinflammation and neurodegeneration in α-synuclein-mediated neurotoxicity Journal of Neuroinflammation tPA α-synuclein Substantia nigra Parkinson’s disease Neuroinflammation Dopaminergic neurons |
| title | The interaction of tPA with NMDAR1 drives neuroinflammation and neurodegeneration in α-synuclein-mediated neurotoxicity |
| title_full | The interaction of tPA with NMDAR1 drives neuroinflammation and neurodegeneration in α-synuclein-mediated neurotoxicity |
| title_fullStr | The interaction of tPA with NMDAR1 drives neuroinflammation and neurodegeneration in α-synuclein-mediated neurotoxicity |
| title_full_unstemmed | The interaction of tPA with NMDAR1 drives neuroinflammation and neurodegeneration in α-synuclein-mediated neurotoxicity |
| title_short | The interaction of tPA with NMDAR1 drives neuroinflammation and neurodegeneration in α-synuclein-mediated neurotoxicity |
| title_sort | interaction of tpa with nmdar1 drives neuroinflammation and neurodegeneration in α synuclein mediated neurotoxicity |
| topic | tPA α-synuclein Substantia nigra Parkinson’s disease Neuroinflammation Dopaminergic neurons |
| url | https://doi.org/10.1186/s12974-025-03336-3 |
| work_keys_str_mv | AT danieltorrente theinteractionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT enmingjsu theinteractionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT alifranciscocitalanmadrid theinteractionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT geraldpschielke theinteractionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT danielmagaoay theinteractionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT markwarnock theinteractionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT tamarastevenson theinteractionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT krismann theinteractionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT flavielesept theinteractionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT nathaliedeletage theinteractionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT manuelblanc theinteractionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT erinhnorris theinteractionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT denisvivien theinteractionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT danielalawrence theinteractionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT danieltorrente interactionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT enmingjsu interactionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT alifranciscocitalanmadrid interactionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT geraldpschielke interactionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT danielmagaoay interactionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT markwarnock interactionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT tamarastevenson interactionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT krismann interactionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT flavielesept interactionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT nathaliedeletage interactionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT manuelblanc interactionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT erinhnorris interactionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT denisvivien interactionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity AT danielalawrence interactionoftpawithnmdar1drivesneuroinflammationandneurodegenerationinasynucleinmediatedneurotoxicity |