Impacts of tissue-type plasminogen activator (tPA) on neuronal survival

Abstract

Tissue-type plasminogen activator (tPA) a serine protease is constituted of five functional domains through which it interacts with different substrates, binding proteins, and receptors. In the last years, great interest has been given to the clinical relevance of targeting tPA in different diseases of the central nervous system, in particular stroke. Among its reported functions in the central nervous system, tPA displays both neurotrophic and neurotoxic effects. How can the protease mediate such opposite functions remain unclear but several hypotheses have been proposed. These include an influence of the degree of maturity and/or the type of neurons, of the level of tPA, of its origin (endogenous or exogenous) or of its form (single chain tPA versus two chain tPA). In this review, we will provide a synthetic snapshot of our current knowledge regarding the natural history of tPA and discuss how it sustains its pleiotropic functions with focus on excitotoxic/ischemic neuronal death and neuronal survival.

Tissue plasminogen activator-based nanothrombolysis for ischemic stroke

“…tPA is a serine protease consisting of 527 or 530 amino-acids with 3 or 4 glycosylation sites and 17 disulfide bonds in its secondary structure 4 . It is released from cells in a single-chain form (sc), but sc-tPA can be cleaved into a mature two-chain form (tc-tPA) by plasmin 5 or kallikrein and factor Xa 6 .…”

“…Each form of tPA has different glycosylation sites: type I tPA glycosylating at Asn117, Asn 184, and Asn448, and type II tPA glycosylating only at Asn117 and Asn448. Of note, different isoforms of tPA (type I sc-tPA, type I tc-tPA, type II sc-tPA, and type II tc-tPA) may display differential properties in terms of the stability, substrate/receptor affinity, and catalytic efficiency 4 . Mature tPA contains 5 different functional domains: a finger domain (F), an epidermal growth factor-like domain (EGF), two kringle domains (K1 and K2), and a serine protease proteolytic domain (SP), in an N-terminal end to C-terminal end order.…”

Is plasminogen activator inhibitor‐1 a physiological bottleneck bridging major depressive disorder and cardiovascular disease?

“…PAI‐1 is also influential in synaptic plasticity (Melchor & Strickland ) via regulation of N‐methyl‐D‐aspartate (NMDA) receptor functionality and expression on the synapse (Chevilley et al . ) (Robinson et al . ).…”

“…Because this brain region strongly projects onto the hypothalamus, it appears that PAI-1 can regulate the physiological response to external stress via the HPA axis. PAI-1 is also influential in synaptic plasticity (Melchor & Strickland 2005) via regulation of N-methyl-D-aspartate (NMDA) receptor functionality and expression on the synapse (Chevilley et al 2015) (Robinson et al 2015). The nature of these interactions is still being elucidated, and it appears that both tPA and PAI-1 may be variably neurotoxic or neurotrophic depending on dose and region of interest.…”

Elevated levels of tissue plasminogen activator and E‐selectin in male children with autism spectrum disorder

“…t‐PA is expressed at high rate in the various brain structures, associated with ASD, including amygdala, hippocampus, and cerebellum (Pothakos et al, ; Zhou, Maiya, Norris, Kreek, & Strickland, ). t‐PA play a role in the physiologic and pathologic processes depending on the level of t‐PA, the type of neuron and the stress paradigm (Chevilley et al, ). Moreover, it contributes to immunomodulation by affecting macrophage migration (Higazi et al, ; Roelofs et al, ).…”