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

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