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Role of proteases in the pathophysiology of neurodegenerative diseases
  1. S Gentleman

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    Edited by Abel Lajtha and Maren L Banik (Pp 302, £59.50). Published by Kluwer Academic/Plenum Publishers, New York, 2001. ISBN 0-306-46579-5

    This volume would be an extremely useful addition to the bookshelf of anybody with an active interest in the biochemical and pathological processes that underlie some of the more common neurological diseases. In the past the role of proteolysis in these disorders has been largely neglected because it was assumed that it represented a general non-specific metabolic process. In terms of attracting research interest the field also suffered from the confusion in the literature concerning the naming of these enzymes and the fact that the same enzyme might have many different names. However, as the editors point out in their preface, this is no longer the case and they have managed to bring together an impressive array of current research on the involvement of proteases in a wide variety of disorders. From what individually might have been regarded as rather disparate studies, one can now start to see common themes not least of which is the potential therapeutic value of targeting specific proteases and the development of specific inhibitors.

    If, like me, you don’t have specialist knowledge of this area I would recommend going straight to the last chapter on the mammalian proteinase genes. Here you will find a clearly laid out summary of the classification and characteristics of the four main groups of proteases (serine, cysteine, aspartic, and metalloproteinases). I also found the chapter on the ubiquitin/proteasome system and the normal physiological breakdown of proteins particularly informative. Having read these two chapters you then have a wide choice of disorders and proteases to choose from. Perhaps the most widely discussed is Alzheimer’s disease, undoubtedly because of the huge advances that have been made in the understanding of the biochemical processes underlying this disease over the past 15 years. Papain-like cysteine proteases (cathepsins), caspases, calpains, and a novel metalloendopeptidase (EC 3.4.24.15) all appear to have some role in the pathology of Alzheimer’s disease and may, therefore, be potential targets for drug development. There is also a group of Alzheimer’s disease specific proteases that affect the processing of the amyloid precursor protein (α, β, and, γ secretase) and presenilin (presenilinase). Both of these proteins are central to the development of pathology and so these enzymes in particular are key targets for current drug company research.

    Apart from the interest in Alzheimer’s disease, there are other chapters covering the role of matrix metalloproteinases and calpain in the demyelination of multiple sclerosis and the key role of calpain in the pathology of traumatic brain and spinal cord injury. Further chapters describe the loss of calcium homeostasis and the subsequent pathological activation of calpain, resulting in the breakdown of key structural proteins in some neuromuscular disorders. In summary, this book has something for everyone in an area of research that holds huge promise for the future in terms of developing useful therapies for treating neurodegenerative disorders.

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