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This volume is concerned with the enzymes of the nervous system. Cerebral enzymes form the basis of the functional brain. They are needed for the control of the energetics of the nervous system, whether it be their release or their direction; for the elaboration of transmitters and for their destruction; for the synthesis, transport, and breakdown of all metabolites of the nervous system. They are indispensable for the control of the multitude of factors that govern our thinking and our behavior. They make it possible for us to comprehend what is taking place around us and perhaps to understand what may be in store for us. Enzymes are the stuff of life, and no living cell can be without them. They are the results of many millions of years of evolution, from the time when biological membranes first came into being and were folded to produce the first cells within which the earliest enzymes were wrought. Countless changes have taken place within them, so that, now, only those enzymes exist that play specific roles in the functions of the living cells of today. Those in the nervous system possess a mUltiple role: in the creation, maintenance, and ultimate breakdown of the component cells and in enabling consciousness, perception, memory, and thought to become possible. But though life may go on forever, the enzymes that make life possible will undergo the many changes involved in the evolutionary process.

This book looks at the role of proteases, which are enzymes that digest proteins, and the various roles that proteases play in the development of neurodegenerative diseases such as Alzheimer's disease, ALS, epilepsy, multiple sclerosis, as well as numerous other neuromuscular diseases.

Researchers seeking problems that offer more hope of success often avoid subjects that seem to be difficult to approach experimentally, or subjects for which experimental results are difficult to interpret. The breakdown part of protein turnover in vivo, particularly in nervous tissue, was such a subject in the past – it was difficult to measure and difficult to explore the mechanisms involved. For factors that influence protein metabolism, it was thought that protein content, function, and distribution are controlled only by the synthetic mechanisms that can supply the needed specificity and response to stimuli. The role of breakdown was thought to be only a general metabolic digestion, elimination of excess polypeptides. We now know that the role of breakdown is much more complex: it has multiple functions, it is coupled to turnover, and it can affect protein composition, function, and synthesis. In addition to eliminating abnormal proteins, breakdown has many modulatory functions: it serves to activate and inactivate enzymes, modulate membrane function, alter receptor channel properties, affect transcription and cell cycle, form active peptides, and much more. The hydrolysis of peptide bonds often involves multiple steps, many enzymes, and cycles (such as ubiquination), and often requires the activity of enzyme complexes. Their activation, modification, and inactivation can thus play an important role in biological functions, with numerous families of proteases participating. The specific role of each remains to be elucidated.

The brain is the organ that collects information from the environment, processes and stores the information, and generates behavior as and when needed. In essence, the brain makes us who we are. For this reason, understanding the biology of brain function is a great challenge and a major goal of modern science. The brain is one of the last great frontiers in science, and the unraveling of its mysteries is comparable in complexity to efforts in space exploration. A fundamental goal of neuroscience is to understand how neurons generate behavior and the pathophysiology of different mental and neurological diseases. This requires, among other things, information about where these neurons are located, how they are connected, and how they communicate with each other in various physiological and pathophysiological conditions. Our aim is to describe recent discoveries about the basic operations of the brain and to provide an introduction to the adaptations for specific types of information processing.

This book looks at the role of proteases, which are enzymes that digest proteins, and the various roles that proteases play in the development of neurodegenerative diseases such as Alzheimer's disease, ALS, epilepsy, multiple sclerosis, as well as numerous other neuromuscular diseases.

Life, either as we think of it in the abstract in its highest sense, or life, as we think of it in terms of a compact living organism, is obviously the result of complex interaction of all of the components of the organism. One could therefore question the advisability of separating out the nervous system for a special detailed study in our age of overspecialization. The main purpose of the present Handbook is not to fragment further our approach or under­ standing of living phenomena, but, on the contrary, to try to summarize and integrate as much of the available information and thinking on the nervous system as is possible in a limited space. It is difficult to think of an area of modern biology that is more exciting to study and that has greater impor­ tance for mankind, from any point of view, than the study of the brain and of the nervous system. The influence that understanding of brain function in biological terms can exert on our future is not generally understood in its full impact. Although our ignorance about even the most basic mechanisms in the nervous system is enormous, in recent years our knowledge has made most important advances, and as a consequence great masses of data have been accumulated.

Life, either as we think of it in the abstract in its highest sense, or life, as we think of it in terms of a compact living organism, is obviously the result of complex interaction of all of the components of the organism.

That chemicals (although not always called by this name) affect the brain and its functions, such as behavior, has been known for thousands of years. It is therefore surprising that the concept that chemical mechanisms are at least partially responsible for the complex functions of the brain is so recent. Investigation of the closely interlinked biophysical and biochemical proper­ ties of the nervous system has achieved many notable successes in recent years and is the most exciting development in 20th-century science. Although all the morphology, the activity, and the alteration of the brain, whether bioelectric, biochemical, pathological, or structural, constitute an organic and indivisible whole, the ambition of the Handbook is to look at only a few aspects of this whole and to focus the discussions on the experi­ ments that the neurochemists have performed. Neurochemical study of the nervous system has, perhaps of necessity, gone through several phases: the first phase was more analytical and in­ volved study of the composition of the tissue; the second, more recent phase clarified many of the metabolic sequences that occur in this tissue. Clearly, both were essential, but they showed that additional approaches are neces­ sary. The present phase seems to be the study of control processes; present interest focuses on what determines, in a qualitative and quantitative fashion, the processes occurring in the nervous system. Perhaps the next phase will be the study of function, the study of the final stage of integration.

That chemicals (although not always called by this name) affect the brain and its functions, such as behavior, has been known for thousands of years. It is therefore surprising that the concept that chemical mechanisms are at least partially responsible for the complex functions of the brain is so recent. Investigation of the closely interlinked biophysical and biochemical proper­ ties of the nervous system has achieved many notable successes in recent years and is the most exciting development in 20th-century science. Although all the morphology, the activity, and the alteration of the brain, whether bioelectric, biochemical, pathological, or structural, constitute an organic and indivisible whole, the ambition of the Handbook is to look at only a few aspects of this whole and to focus the discussions on the experi­ ments that the neurochemists have performed. Neurochemical study of the nervous system has, perhaps of necessity, gone through several phases: the first phase was more analytical and in­ volved study of the composition of the tissue; the second, more recent phase clarified many of the metabolic sequences that occur in this tissue. Clearly, both were essential, but they showed that additional approaches are neces­ sary. The present phase seems to be the study of control processes; present interest focuses on what determines, in a qualitative and quantitative fashion, the processes occurring in the nervous system. Perhaps the next phase will be the study of function, the study of the final stage of integration.

When the projected volumes of the Handbook are completed, most of our current knowledge of the biochemistry of nervous systems will have been touched upon. A number of the chapters will have dealt with the correlations of the biochemical findings with morphological and physio­ logical parameters as well. Considering the abysmal lack of such attempts, even in the recent past, this is a sign of great progress. If the reader''s eventual goal is to derive the "laws" that relate various aspects of animal and human behavior to underlying physiological and biochemical function, these admirable volumes will help him to establish a firm biochemical base from which to operate. It is certain that the future approaches to the various problems of the information-processing functions of the nervous system will require an integrated understanding of the essence of all of the scientific disciplines which are grouped under the general name of neuro­ biology. The rich feast of information offered up in this Handbook will enable those in the non-chemical disciplines to pick and choose those areas of chemical information pertinent to their immediate interests. Similar types of compendia by physiologists, anatomists, cyberneticists, and psychologists have been helpful to chemists and continue to be so.

When the projected volumes of the Handbook are completed, most of our current knowledge of the biochemistry of nervous systems will have been touched upon. A number of the chapters will have dealt with the correlations of the biochemical findings with morphological and physio­ logical parameters as well. Considering the abysmal lack of such attempts, even in the recent past, this is a sign of great progress. If the reader's eventual goal is to derive the "laws" that relate various aspects of animal and human behavior to underlying physiological and biochemical function, these admirable volumes will help him to establish a firm biochemical base from which to operate. It is certain that the future approaches to the various problems of the information-processing functions of the nervous system will require an integrated understanding of the essence of all of the scientific disciplines which are grouped under the general name of neuro­ biology. The rich feast of information offered up in this Handbook will enable those in the non-chemical disciplines to pick and choose those areas of chemical information pertinent to their immediate interests. Similar types of compendia by physiologists, anatomists, cyberneticists, and psychologists have been helpful to chemists and continue to be so.

The explosive accumulation of new knowledge in the biological sciences in the last decades has advanced our understanding of the basic mechanisms that underlie most biological phenomena. These advances, however, have not been uniform but have varied considerably among the different biological problems. In some cases, e.g., biochemical genetics, radical advances have been made which have changed our ideas and our approaches. In other cases, even with work which has yielded much detailed new knowledge, our under­ standing of basic mechanisms remains very inadequate. Among the lines of work that have not yet led to dramatic conceptual advances is the problem of control of biological activities. This problem is, of course, basic both to any full understanding of life as a whole, and to any real understanding of its most minute phenomena. Indeed, the myriad of biological activities that we can observe by direct or indirect means are all under the sway of most exquisitely precise mechanisms. Any malfunctioning of these mechanisms has serious consequences, not only for the particular function itself, but for all the related and interlinked activities.

The explosive accumulation of new knowledge in the biological sciences in the last decades has advanced our understanding of the basic mechanisms that underlie most biological phenomena. These advances, however, have not been uniform but have varied considerably among the different biological problems. In some cases, e.g., biochemical genetics, radical advances have been made which have changed our ideas and our approaches. In other cases, even with work which has yielded much detailed new knowledge, our under­ standing of basic mechanisms remains very inadequate. Among the lines of work that have not yet led to dramatic conceptual advances is the problem of control of biological activities. This problem is, of course, basic both to any full understanding of life as a whole, and to any real understanding of its most minute phenomena. Indeed, the myriad of biological activities that we can observe by direct or indirect means are all under the sway of most exquisitely precise mechanisms. Any malfunctioning of these mechanisms has serious consequences, not only for the particular function itself, but for all the related and interlinked activities.

Anyone who has any contact with mental patients, old or young, or their families, or just visits a mental hospital or school for the retarded, is aware of the tremendous suffering caused by malfunctioning of the brain. The func­ tion of no other organ is so crucial for our everyday life, our proper func­ tioning, indeed our happiness, and no other illness causes as much anguish to patients or their families as mental illness. It is surprising and sad, therefore, how little effort has been devoted to research in this area; more so because such research is the only hope to ameliorate this suffering, or, to speak in the language of politics or economics, to decrease the enormous sums that we spend on trying to help our patients, with what is must generally be agreed are the most primitive and inadequate methods of treatment. Clearly, since functions of the brain are vital not only in illness, but in health, pathology is not the only area of concern to neurochemists, but it is an area that urgently needs neurochemical contributions. Progress in this field has been slower than in other areas of neurochemistry, and it seems that solutions in this field are very elusive. The reason for this is that the experimental approach is especially difficult in conditions specific for humans, or specific for complex behavior.

Anyone who has any contact with mental patients, old or young, or their families, or just visits a mental hospital or school for the retarded, is aware of the tremendous suffering caused by malfunctioning of the brain. The func­ tion of no other organ is so crucial for our everyday life, our proper func­ tioning, indeed our happiness, and no other illness causes as much anguish to patients or their families as mental illness. It is surprising and sad, therefore, how little effort has been devoted to research in this area; more so because such research is the only hope to ameliorate this suffering, or, to speak in the language of politics or economics, to decrease the enormous sums that we spend on trying to help our patients, with what is must generally be agreed are the most primitive and inadequate methods of treatment. Clearly, since functions of the brain are vital not only in illness, but in health, pathology is not the only area of concern to neurochemists, but it is an area that urgently needs neurochemical contributions. Progress in this field has been slower than in other areas of neurochemistry, and it seems that solutions in this field are very elusive. The reason for this is that the experimental approach is especially difficult in conditions specific for humans, or specific for complex behavior.

It has been recognized for more than a thousand years that the function of the brain, like the function of the other organs of the body, is determined by its physical, chemical, and biological properties. Evidence that even its highest functions could be explained by these properties was gathered only in recent years, however; these findings, which clearly have to be confirmed by a great deal of further experimental evidence, indicate that most, if not all, of the functions of the brain are based on its bio­ chemical and biophysical mechanisms. This at first hearing may sound rather simple, but the ability to understand learning, emotion, perhaps even creativity, on biological terms may well be the most important scientific discovery of all time. Few pieces of knowledge can influence our future health and well-being to the degree that understanding of mental mechanisms will. It has been clearly shown in many ways in the previous volumes of this Handbook that from the biochemical or neurochemical point of view the brain is one of the most active organs. The brain seems stable and in some respects permanent; this is evidence not of inactivity but of carefully controlled homeostasis, of dynamic rather than static equilibrium, with most components undergoing metabolic alterations.

It has been recognized for more than a thousand years that the function of the brain, like the function of the other organs of the body, is determined by its physical, chemical, and biological properties. Evidence that even its highest functions could be explained by these properties was gathered only in recent years, however; these findings, which clearly have to be confirmed by a great deal of further experimental evidence, indicate that most, if not all, of the functions of the brain are based on its bio­ chemical and biophysical mechanisms. This at first hearing may sound rather simple, but the ability to understand learning, emotion, perhaps even creativity, on biological terms may well be the most important scientific discovery of all time. Few pieces of knowledge can influence our future health and well-being to the degree that understanding of mental mechanisms will. It has been clearly shown in many ways in the previous volumes of this Handbook that from the biochemical or neurochemical point of view the brain is one of the most active organs. The brain seems stable and in some respects permanent; this is evidence not of inactivity but of carefully controlled homeostasis, of dynamic rather than static equilibrium, with most components undergoing metabolic alterations.

The second volume of the Handbook does not parallel any volume of the first edition; it is one more sign, or reflection, of the expansion of the field. By emphasizing the experimental approach, it illustrates the tools that have re­ cently become available for investigating the nervous system. Also, perhaps even more than other volumes, it illustrates the multidisciplinary nature of the field, requiring multidisciplinary methodology. It is now recognized that the availability of methodology is often the rate-limiting determinant of studies and that improvements or innovations in instrumentation can open up new avenues. A new improved method, although opening up new possibilities and being crucial to making advances, is only a tool whose use will determine its use­ fulness. If we do not recognize its possibilities, its use will be limited; if we do not recognize its limitations, it will mislead us. It is the possibilities and limitations and the results obtained that are illustrated here.

The second volume of the Handbook does not parallel any volume of the first edition; it is one more sign, or reflection, of the expansion of the field. By emphasizing the experimental approach, it illustrates the tools that have re­ cently become available for investigating the nervous system. Also, perhaps even more than other volumes, it illustrates the multidisciplinary nature of the field, requiring multidisciplinary methodology. It is now recognized that the availability of methodology is often the rate-limiting determinant of studies and that improvements or innovations in instrumentation can open up new avenues. A new improved method, although opening up new possibilities and being crucial to making advances, is only a tool whose use will determine its use­ fulness. If we do not recognize its possibilities, its use will be limited; if we do not recognize its limitations, it will mislead us. It is the possibilities and limitations and the results obtained that are illustrated here.

This volume is concerned with metabolic reactions occurring in the nervous system. Some time ago, it was thought that since most of the intermediary metabolism that can be observed in the brain is not specific to this organ, there is little justification in studying neural metabolism as such. Later it was realized that for an understanding of neural functions, the understanding of metabolism in the brain and its alterations is essential. All aspects of the metabolism of a substrate in brain, or all metabolic reactions of the nervous system, could not be included in this volume; some will be dealt with in other volumes (such as the ones covering metabolic turn­ over, alterations of metabolism, or pathology). Review of the aspects covered here clearly shows that the study of metabolic reactions in the nervous system is a very active field, producing important results. As in so many areas of research, as we learn more, new aspects become known, new questions emerge, and we see that in solving some problems we open areas with many additional problems to solve. But the accomplishments to date are impressive and indicate further important advances in the future. Brain metabolism is more active, more plastic, and more comprehensive than previously estimated. It is an essential part of brain function, and with its alteration, brain function will be altered. This shows the importance of more knowledge in this area. It is hoped that this volume will be of assistance in such further studies.

This volume is concerned with metabolic reactions occurring in the nervous system. Some time ago, it was thought that since most of the intermediary metabolism that can be observed in the brain is not specific to this organ, there is little justification in studying neural metabolism as such. Later it was realized that for an understanding of neural functions, the understanding of metabolism in the brain and its alterations is essential. All aspects of the metabolism of a substrate in brain, or all metabolic reactions of the nervous system, could not be included in this volume; some will be dealt with in other volumes (such as the ones covering metabolic turn­ over, alterations of metabolism, or pathology). Review of the aspects covered here clearly shows that the study of metabolic reactions in the nervous system is a very active field, producing important results. As in so many areas of research, as we learn more, new aspects become known, new questions emerge, and we see that in solving some problems we open areas with many additional problems to solve. But the accomplishments to date are impressive and indicate further important advances in the future. Brain metabolism is more active, more plastic, and more comprehensive than previously estimated. It is an essential part of brain function, and with its alteration, brain function will be altered. This shows the importance of more knowledge in this area. It is hoped that this volume will be of assistance in such further studies.

A major advance in the biological sciences in the past decade has been the biochemical identification of cell membrane receptors. The existence of re­ ceptor substances on the surface of cells that recognize and bind to extracellular molecules was proposed at the beginning of the century by the pharmacologist and immunologist Paul Ehrlich and the physiologist J. N. Langley. Since then, receptors have been found to play an important role in numerous physiological and pathological processes. Over the years many attempts have been made to physically isolate and chemically characterize receptors, but because of the receptors'' extremely low concentration and membrane localization, these ef­ forts have met with limited success. Yet, despite the failure to characterize receptor substances, the concept of the presence of such molecules has had considerable heuristic value. Using pharmacological, physiological, and im­ munologic approaches, researchers have identified several specific receptors, e. g. , a-and ~-adrenergic, nicotinic and muscarinic cholinergic, and histami­ nergic. With the characterization of various types of receptors on cell mem­ branes, many drugs were developed that proved to be experimentally and ther­ apeutically useful. It was only in the early 1970s that methods for the specific measurement, chemical characterization, and physical isolation of cell membrane receptors were developed. These advances were made possible by the availability of ligands with high specific radioactivity that retained their biological activity and of experimental procedures that differentiated between specific and non­ specific binding of ligands.

A major advance in the biological sciences in the past decade has been the biochemical identification of cell membrane receptors. The existence of re­ ceptor substances on the surface of cells that recognize and bind to extracellular molecules was proposed at the beginning of the century by the pharmacologist and immunologist Paul Ehrlich and the physiologist J. N. Langley. Since then, receptors have been found to play an important role in numerous physiological and pathological processes. Over the years many attempts have been made to physically isolate and chemically characterize receptors, but because of the receptors' extremely low concentration and membrane localization, these ef­ forts have met with limited success. Yet, despite the failure to characterize receptor substances, the concept of the presence of such molecules has had considerable heuristic value. Using pharmacological, physiological, and im­ munologic approaches, researchers have identified several specific receptors, e. g. , a-and ~-adrenergic, nicotinic and muscarinic cholinergic, and histami­ nergic. With the characterization of various types of receptors on cell mem­ branes, many drugs were developed that proved to be experimentally and ther­ apeutically useful. It was only in the early 1970s that methods for the specific measurement, chemical characterization, and physical isolation of cell membrane receptors were developed. These advances were made possible by the availability of ligands with high specific radioactivity that retained their biological activity and of experimental procedures that differentiated between specific and non­ specific binding of ligands.

Neurochemistry, having the objective of elucidating biochemical processes subserving nervous activity, emerged as an application of chemistry to the of neurobiological problems as a post-World War II phenomenon. investigation However, only in the last 40 years has the chemical community recognized neurochemistry as a distinct, if hybrid, discipline. During this period great strides have been made. However, recently neurochemistry, along with neu­ rophysiology, neuropharmacology, neuroanatomy, and the behavioral sci­ ences, has emerged to form neuroscience, a new community of scientists with its own national society, journals, and meetings. Actually, this recently formed hybrid, neuroscience, is in the process of merging with another well-established discipline, molecular genetics (frequently called molecular biology, and itself a hybrid), which appears to have sufficient hybrid vigor to form yet a new community of scientists, which, for want of a more imaginative term, has been called molecular genetic neuroscience. Clearly, advantages resulting from such mergers or hybridizations accrue not only from the merging discipline (neurochemistry in this case) to the new community (molecular genetic neuroscience), but also in the reverse direction. This Foreword will be concerned primarily with examples of this latter process.

Neurochemistry, having the objective of elucidating biochemical processes subserving nervous activity, emerged as an application of chemistry to the of neurobiological problems as a post-World War II phenomenon. investigation However, only in the last 40 years has the chemical community recognized neurochemistry as a distinct, if hybrid, discipline. During this period great strides have been made. However, recently neurochemistry, along with neu­ rophysiology, neuropharmacology, neuroanatomy, and the behavioral sci­ ences, has emerged to form neuroscience, a new community of scientists with its own national society, journals, and meetings. Actually, this recently formed hybrid, neuroscience, is in the process of merging with another well-established discipline, molecular genetics (frequently called molecular biology, and itself a hybrid), which appears to have sufficient hybrid vigor to form yet a new community of scientists, which, for want of a more imaginative term, has been called molecular genetic neuroscience. Clearly, advantages resulting from such mergers or hybridizations accrue not only from the merging discipline (neurochemistry in this case) to the new community (molecular genetic neuroscience), but also in the reverse direction. This Foreword will be concerned primarily with examples of this latter process.