The serine proteases and their function in neuronal death processes

In this review we analyse the role played by the serine proteases in the nervous system and we focus on the role they play in degenerative processes. These proteolytic enzymes, together with the caspases, play a vital role in the processes regulating cell functioning, both in the development stages and following the response to a harmful stimulus. This family of proteases includes the granzymes and thrombin (TR). The former, which are closely related to proteases I and II and cathepsin G, are situated in the cytoplasmic granules of the activated T lymphocytes, together with other proteins such as perforin or cytolysin. Granzymes A and B are linked to degenerative processes. These enter the target cells thanks to the action of perforin and once inside they are translocated to the nucleus. Granzyme A has been isolated and identified as the agent responsible for the immediate and complete retraction of neurites in different models. Its physiological substrates include fibronectin, type IV collagen and the proteoglycans. Granzyme B is characterised by its being a cysteine protease with substrates such as prointerleukin 1 beta, TR receptor and poly(ADP ribose) polymerase. The family of TR type proteases includes proteases such as TR itself, plasmin, kallikrein, urokinase plasminogen activator and tissue plasminogen activator. TR is considered to be an early modulator in damaged tissues which acts as an extracellular signal of death, leading to the activation of intracellular mechanisms that appear to be mediated by calcium. Serine protease activity is regulated by endogenous inhibitors, such as plasminogen activator inhibitor, protease nexin 1 and neuroserpin. Upsets in the protease inhibitor balance are crucial in the processes involved in the neuronal plasticity and death induced by ischemia in the brain and by excitotoxins.