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Tissue Plasminogen Activator Interaction with NMDAR1 Promotes Dopaminergic Neuron Degeneration in a Model of Α-Synuclein-Mediated Neurotoxicity

66 Pages Posted: 16 Mar 2022 Publication Status: Review Complete

See all articles by Daniel Torrente

Daniel Torrente

University of Michigan Medical School

Enming J. Su

University of Michigan Medical School

Gerald P. Schielke

University of Michigan Medical School

Mark Warnock

University of Michigan Medical School

Tamara Stevenson

University of Michigan Medical School

Kris Mann

University of Michigan Medical School

Denis Vivien

Sorbonne University - Institut du Cerveau-Paris Brain Institute (ICM)

Daniel A. Lawrence

University of Michigan Medical School - Department of Molecular & Integrative Physiology

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Abstract

The protease tissue plasminogen activator (tPA) is linked to diverse functions in the central nervous system. Here we characterize the expression and localization of tPA in the substantia nigra (SN) and explore the role of tPA in dopaminergic neuron degeneration in a human α-synuclein (hα-SYN) mouse model of Parkinson's disease. We found that striatal GABAergic neurons send tPA + axons that innervate the SN proximal to dopaminergic neuronal cell bodies and axons. tPA deficiency protected dopaminergic neurons from degeneration and reversed behavioral deficits induced by hα-SYN-induced neurotoxicity. tPA’s action was independent of its proteolytic activity, and could be blocked by treatment with Glunomab, a neutralizing antibody that selectively inhibits tPA interaction with N-methyl-D-aspartate receptor-1. Both tPA deficiency and Glunomab treatment prevented neuronal degeneration, and reduced microglia activation and T-cell infiltration. Together, these data demonstrate a previously unrecognized pathway promoting dopaminergic neuronal degeneration and suggest a potential therapeutic intervention with Glunomab.

Keywords: tPA, α-Synuclein, substantia nigra, Parkinson Disease, dopaminergic neurons, NMDAR, Glunomab, neuroinflammation, Microglia, T-cell

Suggested Citation

Torrente, Daniel and Su, Enming J. and Schielke, Gerald P. and Warnock, Mark and Stevenson, Tamara and Mann, Kris and Vivien, Denis and Lawrence, Daniel A., Tissue Plasminogen Activator Interaction with NMDAR1 Promotes Dopaminergic Neuron Degeneration in a Model of Α-Synuclein-Mediated Neurotoxicity. Available at SSRN: https://ssrn.com/abstract=4059525 or http://dx.doi.org/10.2139/ssrn.4059525
This version of the paper has not been formally peer reviewed.

Daniel Torrente

University of Michigan Medical School ( email )

Ann Arbor, MI
United States

Enming J. Su

University of Michigan Medical School ( email )

Ann Arbor, MI
United States

Gerald P. Schielke

University of Michigan Medical School ( email )

Ann Arbor, MI
United States

Mark Warnock

University of Michigan Medical School ( email )

Ann Arbor, MI
United States

Tamara Stevenson

University of Michigan Medical School ( email )

Ann Arbor, MI
United States

Kris Mann

University of Michigan Medical School ( email )

Ann Arbor, MI
United States

Denis Vivien

Sorbonne University - Institut du Cerveau-Paris Brain Institute (ICM) ( email )

Paris
France

Daniel A. Lawrence (Contact Author)

University of Michigan Medical School - Department of Molecular & Integrative Physiology ( email )

7744 MS II
1137 E. Catherine St.
Ann Arbor, MI 48109-5622
United States

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