Table Of ContentSerine Proteases and
Their Serpin Inhibitors
in the Nervous System
Regulation in Development and in
Degenerative and Malignant Disease
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Volume 191-Serine Proteases and Their Serpin Inhibitors
in the Nervous System:
Regulation in Development and in Degenerative and
Malignant Disease
edited by Barry W. Festoff
Series A: Life Sciences
Serine Proteases and
Their Serpin Inhibitors
in the Nervous System
Regulation in Development and in
Degenerative and Malignant Disease
Edited by
Barry W. Festoff
University of Kansas and
Kansas City Veterans Affairs Medical Centers
Kansas City, Missouri
Associate Editor
Daniel Hanta'j
INSERM
Paris, France
Plenum Press
New York and London
Published in cooperation with NATO Scientific Affairs Division
Proceedings of a NATO Advanced Research Workshop on
Regulation of Extravascular Fibrinolysis if!
Nervous System Development and Disease,
held July 2-8, 1989,
in Maratea, Italy
Library of Congress Cataloging in Publication Data
NATO Advanced Research Workshop on Regulation of Extravascular Fibrino
lysis in Nervous System Development and Disease (1989: Maratea, Italy)
Serine proteases and their serpin inhibitors in the nervous system: regulation
in development and in degenerative and malignant disease I edited by Barry W.
Festoff associate editor, Daniel Hantai.
p. cm.-(NATO ASI series. Series A, Life sciences; v. 191)
"Proceedings of a NATO Advanced Research Workshop on Regulation of Ex
travascular Fibrinolysis in Nervous System Development and Disease, held July
2-8,1989, in Maratea, Italy"-T.p. verso.
"Published in cooperation with NATO Scientific Affairs Division."
Includes bibliographical references.
Includes index.
ISBN 978-1-4684-8359-8 ISBN 978-1-4684-8357-4 (eBook)
DOI 10.1007/978-1-4684-8357-4
1. Serine proteinases-Congresses. 2. Serpins-Congresses. 3. Fibrinolysis
Congresses. 4. Nervous system-Growth-Congresses. 5. Nervous system
Pathophysiology-Congresses. I. Festoff, Barry W. II. Hantai, Daniel. III. North
Atlantic Treaty Organization. Scientific Affairs Division. IV. Title. V. Series.
[DNLM: 1. Fibrinolysis-congresses. 2. Nervous System-growth & develop
ment-congresses. 3. Nervous System Diseases-pathology-congresses. 4.
Plasminogen Activators-congresses. 5. Serine Proteinases-physiology
congresses. 6. Serpins-physiology-congresses. QU 136 N279s 1989]
QP609.S47N37 1989
616.8'0471-dc20
DNLM/DLC 90-7453
for Library of Congress CIP
© 1990 Plenum Press, New York
A Division of Plenum Publishing Corporation
233 Spring Street, New York, N.Y. 10013
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, photocopying, microfilming,
recording, or otherwise, without written permission from the Publisher
Softcover reprint of the hardcover 1s t edition 1990
To Shea and Mara
-B.W.F.
THE MARATEA CONFERENCE
Organization Committee
Barry W. Festoff, M.D. University of Kansas Medical Center at the
Director Veterans Administration Medical Center,
Kansas City, MO 64128 USA
Georgia Barlovatz-Meimon, Ph.D. Universite Paris XII (Val de Marne)
Creteil, FRANCE
Robin Carrell, M.D. University of Cambridge Clinical School
Cambridge CB2 2QL UNITED KINGDOM
Daniel Hantai, M.D., Ph.D. I.N.S.E.R.M. Unite 153,
75005 Paris, FRANCE
Gustave Moonen, M.D., Ph.D. Universite de Liege
Liege, BELGIUM
vii
SPONSORS
NATO DIVISION OF SCIENTIFIC AFFAIRS
ABBOTT lABORATORIES
ALS MND RESEARCH FOUNDATION
AMVESTORS FINANCIAL CORPORATION
ARMY MEDICAL RESEARCH COMMAND
ASSOCIATION FRAN<;AISE CONTRE LES MYOPATHIES
ATHENA NEUROSCIENCES
BAYERAG
BOEHRINGER INGELHEIM AG
CIBA-GEIGY AG
CNS RESEARCH, INC.
DELTA BIOTECHNOLOGY (UK)
E.I. DUPONT DE NEMOURS & CO., INC.
LILLY RESEARCH lABORATORIES
FONDAZIONE SIGMA TAU
GENENTECH, INC.
GLAXO RESEARCH lABORATORIES
INVITRON CORPORATION
KABI, FRANCE
MARATEA E BASILICATA AZIENDA TURISMO
MARION lABORATORIES, INC.
NEUROLOGICAL & PSYCHIATRIC RESEARCH & TREATMENT FOUNDATION
PFIZER INC.
SANDOZ, FRANCE
SCHERINGAG
SCHERING CORPORATION
SIGMA TAU
SWINGSTERS, INC
THE UPJOHN COMPANY
U.S. DEPARTMENT OF VETERANS AFFAIRS
ix
"Now here, you see, it takes all the running you can do,
to keep in the same place. If you want to get
somewhere else, you must run at least twice as fast as
that!"
THE RED QUEEN TO ALICE
LEWIS CARROLL
THROUGH THE LOOKING GLASS
SERINE PROTEASES AND THEIR INHIBITORS IN THE NERVOUS SYSTEM
When we decided, in the Fall of 1988, to hold a NATO Advanced Research
Workshop on the topic of the possible roles and regulation of serine proteases and
their high molecular weight inhibitors, the serpins, in the nervous system we had no
idea just how fast this fledgling field was developing. Just six months before, the
simultaneous publication of the presence of a Kunitz-type protease inhibitor domain
in the f3 amyloid precursor protein occurred. The isolation and purification of this
molecule had only been published in 1984, the cloning of the gene just three years
later. It was only in 1983 that the glial-derived neurite promoting factor was shown
by Denis MONARD and his colleagues to be a fibrinolytic protease inhibitor and only
in 1986 that it was similar to protease nexin (re-named protease nexin I). Protease
nexin I itself was first reported by Joffre BAKER and Dennis CUNNINGHAM and
their colleagues, to be made by human foreskin fibroblasts in 1980 and by our lab in
clonal mouse muscle cells in 1981. It was not until 1987 that the cloning of the cDNA
for the glial factor showed that it was identical to protease nexin I except for three
amino acids and that protease nexin I was almost as good a promoter of neurite
outgrowth as was the glial factor. In 1988 it was confirmed by Michael McGROGAN,
Randy SCOTT and BAKER that the two molecules were virtually identical and that
two forms of protease nexin I were produced by fibroblasts, the a and f3 forms, while
only the f3 form was synthesized by astrocytes.
In the meantime, reports of the activity and possible roles of serine proteases in
neural development, both in the periphery as well as in the central nervous system,
were appearing. The remodelling that occurs in developing and regenerating tissues
was not absent from the nervous system and several laboratories, notably those of
xi
Nicholas SEEDS, Nurit KALDERON, Gustave MOONEN, Randall PITTMAN and
our own, endeavored to show the effects of such enzymes in these tissue kinetic
situations. Urokinase and tissue plasminogen activator levels were estimated and
relative specificity for either the PNS, both nerve and neuromuscular, or CNS were
found. The possible involvement of these proteases, along with their cell-surface
receptors was just being explored in other remodelling and motility conditions and was
being sought for in neural remodelling and development.
Fibrinolysis, and its control, had received little attention until recently in the
pathogenesis of human primary brain tumors. This area has just begun to be of
interest to clinicians, primarily neurosurgeons, and is likely to receive continued
attention in the future. Raymond SAWAYA and his associates, and Jasti RAO in our
laboratory, have focused on the balance of serine proteases and inhibitors in glioma
pathogenesis and possible treatment.
The initial idea for the Workshop had its seed planted on both sides of the Seine
during a delightful and productive sabbatical year we spent in Paris. It actually began
one cold and wet December night in 1984 at the Brasserie Lipp when, under the
influence of our then not-quite-three-year-old daughter, Mara, I met Professor H.
Coen HEMKER of the University of Maastricht. He, in tum, introduced me to those
delightful,-and always helpful, sisters Jeannette and Claudine SORIA. Together with
my then-new co~.league in Professor Michel FARDEAU'S I.N.S.E.R.M. Unite 153,
Daniel HANTAI, we extended our studies on the serine protease:serpin balance in
the neuromuscular system, which continue on both sides of the Atlantic today.
We sought to organize the program of the meeting to bring together experts in
the biochemistry and molecular biology of fibrinolysis and protease inhibition with
those in neurobiology who might not have had previous occasions to come together.
Some of our critics, perhaps influenced by other claims of fusion then extant in the
lay press, said it was unlikely to be accomplished. After the first day, with numerous
arrival mishaps, including the perennial strikes on the Italian rail system and others,
we were not sure, ourselves, whether it would come off right. However, in another
24 hours, the ambience of the place and the hospitality of the staff of the Hotel Villa
del Mare, began to work their magic on the participants so that, ultimately, most came
away from THE MARATEA CONFERENCE with a truly remarkable feeling that
they had experienced something new, unique and exciting. We are now convinced of
this achievement and hope that the final product of this unique research workshop,
this book, will convey those sentiments to the reader and, at the same time, stand as
a reference book for some time chronicling, in fact, the launching of this field of
protease regulation in neurobiological situations.
As editor, I amJndebted to the members of the Organizing Committee, especially
to Daniel HANTAI, who also served as associate editor, and to Robin CARRELL,
who saw the "wisdom" of proceeding with such a workshop at this time. We are
grateful to all the speakers at the Workshop for their timeliness in providing their
manuscripts and to their secretaries and typists for their willingness in sending both
hard copies as well as floppy disks in usable formats. By so doing we have been able
to edit, correct and print this book in the shortest possible time. The credit for this
book goes to them, while if any imperfections should be found, we take total
responsibility for all. Thanks are due to our word processor assistant, Joyce CAPPS
and to our editorial assistants, Julie ALEXANDER and Pamela GILFORD in Kansas
City. I'd also like to thank Drs. Jasti RAO and Rajendra REDDY and Riichiro
SUZUKI, of the Neurobiology Research Lab, for their untiring support throughout
the entire process.
We gratefully acknowledge the financial support of all those organizations listed
on the SPONSORS page, without which we could not have accomplished this
Workshop. Dr. Craig SINCLAIR, of NATO's ARW Programme, was very supportive,
along with Dr. BARTOWMUCCI of FONDAZIONE SIGMA TAU and Dr.
Friederich SCHUMANN of BAYER AG, who helped to defray some of the costs of
preparing the final edited manuscript for publication. We wish to thank Melanie
xii
YEUTY and Gregory SAFFORD of PLENUM PUBLICATIONS in New York for
their advice and assistance. On behalf of all the participants, we finally wish to thank
Sr. A GUZZARDI, his son, Giacomo, and the staff of the Hotel Villa Del Mare
along with Madame T. IANNINI and her staff of the AZIENDA AUTOMNA
SOGGIORNO E TURISMO DE MARATEA for transmuting a research meeting
in their quaint seaside village into a truly memorable experience we will always
treasure.
Barry W. Festoff
Kansas City, Fall 1989
xiii
