oa Editorial [Hot Topic: Prolyl Oligopeptidase in Brain Function and Dysfunction (Guest Editor: J. Arturo Garcia-Horsman)]

Soon after its discovery during early seventies, prolyl oligopeptidase (abbreviated PREP, POP, PO, or PEP) was shown to cleave neuroactive peptides. This finding hinted that the peptidase would have an important role in controlling the physiological neuropeptide levels and thus, its inhibition would have a direct consequence on central nervous system function modifying mood, behaviour, perception and its processing, or memory. This rationale guided the first efforts to develop specific inhibitors already during the late seventies. Subsequent to this, and after it was described that PREP inhibitors would counteract memory loss caused by chemical insults or brain ischemia, the search for potent compounds boomed, particularly in Japan. Indications that PREP inhibitors were neuroprotective, further fueled the interest of pharmaceutical companies to dedicate resources towards the development of a drug efficient for brain PREP inhibition. Patent applications were then filled to cover compounds indicated for dementia and neurodegeneration. However, the role of PREP in neuropeptide metabolism has been difficult to establish, and the search for the physiological relevance of the peptidase has been a task difficult to achieve. This special issue of CNS & Neurological Disorders-Drug Targets aims to provide a critical review of the research on PREP and delineate new ways this intriguing enzyme might be working not only in the brain, but also in the periphery. Contributions to this issue revise basic information on PREP structure (see Rea and Fulop) and its relation with function (see van Elzen and Lambeir). Essential to understand PREP's function is the determination of its physiological substrates (see Tenorio-Laranga, et al.) on one hand, as well as the physical and functional localization of PREP in the brain (see Peltonen, et al.), on the other. More evidence is emerging pointing to PREP having roles connected to intracellular signalling and transport (see Harwood, and also Moravski, et al.) in which direct protein interactions ( see Lambeir) might be of relevance. The relationship of PREP and disease is also reviewed, not only in connection with dementias, but also with pathologies with an inflammatory component (see Penttinen et al). To the eye of a molecular scientist, the size and structure of PREP indicates a function beyond a simple peptidase. Serine proteases have a small, compact α/β-hydroxylase folded structure, but PREP is provided with an extra propeller domain of uncertain function. It seems of some consensus that PREP possesses a non-hydrolase function. This is also strongly suggested from the study of a structurally related protein, PREPL, of an apparently non-peptidase activity but with profound health consequences over its genetic disturbance (see Boonen, et al.). With regard to the drug target importance of PREP, it seems even more interesting scenarios are emerging on this respect and more research might be stimulated from now. In this enterprise, funding, as the one obtained from the 7th Framework programme of the European Commission for most of the research on PREP described in this issue, has been fundamental, as well as the interest of CNS & Neurological Disorders-Drug Targets editorial managing to disseminate the outcome of this research.