Physiological and pathological functions of neuroserpin: Regulation of cellular responses through multiple mechanisms

It is 27 years since neuroserpin was first discovered in the nervous system and identified as a member of the serpin superfamily. Since that time potential roles for this serine protease inhibitor have been identified in neuronal and non-neuronal systems. Many are linked to inhibition of neuroserpin's principal enzyme target, tissue plasminogen activator (tPA), although some have been suggested to involve alternate non-inhibitory mechanisms. This review focuses mainly on the inhibitory roles of neuroserpin and discusses the evidence supporting tPA as the physiological target. While the major sites of neuroserpin expression are neural, endocrine and immune tissues, most progress on characterizing functional roles for neuroserpin have been in the brain. Roles in emotional behaviour, synaptic plasticity and neuroprotection in stroke and excitotoxicity models are discussed. Current knowledge on three neurological diseases associated with neuroserpin mutation or activity, Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB), Alzheimer's disease and brain metastasis is presented. Finally, we consider mechanistic studies that have revealed a distinct inhibitory mechanism for neuroserpin and its possible implications for neuroserpin function.