NEUROSERPIN, A BRAIN-ASSOCIATED INHIBITOR OF TISSUE-PLASMINOGEN ACTIVATOR IS LOCALIZED PRIMARILY IN NEURONS - IMPLICATIONS FOR THE REGULATION OF MOTOR LEARNING AND NEURONAL SURVIVAL

A cDNA clone for the serine proteinase inhibitor (serpin), neuroserpin , was isolated from a human whole brain cDNA library, and recombinant protein was expressed in insect cells, The purified protein is an effi cient inhibitor of tissue type plasminogen activator (tPA), having an apparent second-order rate constant of 6.2 x 10(5) M-1 s(-1) for the t wo-chain form. However, unlike other known plasminogen activator inhib itors, neuroserpin is a more effective inactivator of tPA than of urok inase-type plasminogen activator, Neuroserpin also effectively inhibit ed trypsin and nerve growth factor-gamma but reacted only slowly with plasmin and thrombin, Northern blot analysis showed a 1.8 kilobase mes senger RNA expressed predominantly in adult human brain and spinal cor d, and immunohistochemical studies of normal mouse tissue detected str ong staining primarily in neuronal cells with occasionally positive mi croglial cells. Staining was most prominent in the ependymal cells of the choroid plexus, Purkinje cells of the cerebellum, select neurons o f the hypothalamus and hippocampus, and in the myelinated axons of the commissura, Expression of tPA within these regions is reported to be high and has previously been correlated with both motor learning and n euronal survival, Taken together, these data suggest that neuroserpin is likely to be a critical regulator of tPA activity in the central ne rvous system, and as such may play an important role in neuronal plast icity and/or maintenance.