Molecular and Cell Biology of Neuropsychiatric Diseases

210 Pages·1994·12.801 MB·English

by  David Craufurd (auth.), Frank Owen, Ruth Itzhaki (eds.)

Molecular and Cell Biology of
Neuropsychiatric Diseases
Molecular and Cell Biology of Human Diseases Series
Series Editors
D.].M. WRIGHT MD FR ePath
Reader in Medical Microbiology,
Charing Cross and Westminster School, London, UK
L.c. ARCHARD PhD
Senior Lecturer in Biochemistry,
Charing Cross and Westminster Medical School, London, UK
The continuing developments in molecular biology have made possible a
new approach to a whole range of different diseases. The books in this series
each concentrate on a disease or group of diseases where real progress is
being made in understanding the pathogenesis, diagnosis and management.
Experts on aspects of each area provide a text accessible to scientists and
clinicians in a form which records advances and points to the potential
application of these advances in a clinical setting.
Other titles in this series
1 Molecular and Cell Biology of Sexually Transmitted Diseases
Edited by David Wright and Leonard Archard
2 Molecular and Cell Biology of Opportunistic Infections in AIDS
Edited by Steven Myint and Alan Cann
3 Molecular and Cell Biology of Muscular Dystrophy
Edited by Terence Partridge
Molecular and Cell Biology of
N europsychiatric Diseases
EDITED BY
Frank Owen
Department of Physiology,
University of Manchester, UK
AND
Ruth Itzhaki
Department of Optometry and Vision Sciences,
UMIST, UK
Springer-Science+Business Media, B.V.
First edition 1994
© 1994 Springer Science+Business Media Dordrecht
Originally published by Chapman & Hali in 1994
Typeset in 10112 Sabon by Florencetype Ltd, Kewstoke, Avon
ISBN 978-94-010-4305-2 ISBN 978-94-011-0709-9 (eBook)
DOI 10.1007/978-94-011-0709-9
Apart from any fair dealing for the purposes of research or private study, or
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1988, this publication may not be reproduced, stored, or transmitted, in any form
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The publisher makes no representation, express or implied, with regard to the
accuracy of the information contained in this book and cannot accept any legal
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A catalogue record for this book is available from the British Library
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Printed on acid-free text paper, manufactured in accordance with ANSIINISO
Z39.48-1992 (Permanence of Paper).
Contents
List of contributors IX
1 Molecular biology of Huntington's disease
DAVID CRAUFURD 1
1.1 Introduction 1
1.2 Linkage analysis 3
1.3 Recombination events 5
1.4 Linkage disequilibrium 6
1.5 Genomic imprinting 9
1.6 Predictive testing 11
1.7 Ethical considerations 13
1.8 Uptake of predictive testing 15
1.9 Counselling 17
1.10 Conclusion 19
References 19
2 Neuronal pathology in relation to molecular biology and
treatment of Alzheimer's disease
PAUL T. FRANCIS and DAVID M. BOWEN 25
2.1 Introduction 25
2.2 Neurotransmission 28
2.3 Glutamate, excitotoxicity and l3-amyloid 36
2.4 Drug therapies 38
2.5 Conclusions 43
References 44
3 The aetiology of Alzheimer's disease
RUTH F. ITZHAKI 55
3.1 General introduction 55
3.2 Aluminium 55
3.3 Viruses 72
v
CONTENTS
3.4 DNA repair 76
3.5 Other possible risk factors 80
3.6 Epilogue 81
Acknowledgements 82
References 82
4 The molecular genetics of Alzheimer's disease
MICHAEL J. OWEN 92
4.1 Introduction 92
4.2 Genetic epidemiology 94
4.3 The molecular genetics of Alzheimer's disease 98
4.4 Future studies 104
References 105
5 The molecular biology of the transmissible dementias
110
FRANK OWEN
5.1 Introduction 110
5.2 The infectious agent 111
5.3 The PrP gene and its expression 112
5.4 The PrP 113
5.5 Molecular genetics of the human transmissible dementias 116
5.6 Summary and concluding remarks 126
References 126
6 The neurochemistry of schizophrenia
FRANK OWEN and MICHAEL SIMPSON 133
6.1 Serotonergic function in schizophrenia 133
6.2 Central noradrenergic function in schizophrenia 135
6.3 Dopamine and schizophrenia 136
6.4 Monoamine oxidase and schizophrenia 139
6.5 GABAergic function in schizophrenia 141
6.6 Neuropeptidergic function in schizophrenia 141
6.7 Glutamatergic systems in schizophrenia 144
6.8 Conclusions 148
References 148
7 Molecular biology of schizophrenia
DAVID ST CLAIR, W AL TER MUIR and DOUGLAS BLACKWOOD 160
7.1 Introduction 160
7.2 Linkage studies 165
7.3 Cytogenetic anomalies and schizophrenia 166
7.4 Mutation analysis in schizophrenia 168
VI
CONTENTS
7.5 Summary 169
References 169
8 Genetics and molecular biology of manic-depression
MICHAEL GILL 173
8.1 Introduction 173
8.2 Clinical diagnosis and identification of the phenotype 174
8.3 Clinical genetics and models of transmission 176
8.4 Models of genetic transmission 179
8.5 Biological theories and possible candidate genes 180
8.6 Gene finding methods: genetic linkage and allelic
associ a tion 184
8.7 Genetic (allelic) association analysis and its use in
the major psychoses 187
References 189
Index 194
VB
Contributors
Douglas Blackwood Michael Gill
MRC Human Genetics Unit Institute of Psychiatry
Western General Hospital DeCrespigny Park
Crewe Road Denmark Hill
Edinburgh EH4 2XU London SE5 8AF
UK UK
David M. Bowen
Ruth F. Itzhaki
Miriam Marks Department of
Molecular Neurobiology
Neurochemistry
Laboratory
Institute of Neurology
Department of Optometry and
1 Wakefield Street
Vision Sciences
London WCIN IP]
UMIST
UK
Manchester M60 1 QD
UK
David Craufurd
University of Manchester
Walter Muir
School of Psychiatry and
MRC Human Genetics Unit
Behavioural Sciences
Western General Hospital
Rawnsley Building
Crewe Road
Manchester Royal Infirmary
Edinburgh EH4 2XU
Oxford Road
UK
Manchester M 13 9WL
UK
Frank Owen
Paul T. Francis Department of Physiological
Miriam Marks Department of Sciences
Neurochemistry University of Manchester
Institute of Neurology Stop ford Building
1 Wakefield Street Oxford Road
London WCIN IP] Manchester M 13 9PT
UK UK
IX
CONTRIBUTORS
J.
Michael Owen David St Clair
Departments of Psychological MRC Human Genetics Unit
Medicine and Medical Genetics Western General Hospital
University of Wales College of Crewe Road
Medicine Edinburgh EH4 2XU
Heath Park UK
Cardiff CF4 4XN
UK
Michael Simpson
Department of Physiological
Sciences
University of Manchester
Stopford Building
Oxford Road
Manchester M13 9PT
UK
x
OJ
Molecular biology of
Huntington's disease
DAVID CRAUFURD
1.1 INTRODUCTION
Huntington's disease (HD) is a chronic, degenerative disorder of the central
nervous system. It takes its name from George Huntington, a North
American physician who first described the characteristic features (Hunt
ington, 1872), which include chorea, generalized impairment of motor
function and dementia. The onset of symptoms is usually delayed until the
fourth or fifth decade of life, but thereafter the disorder follows a pro
gressive course leading eventually to death after an interval of about 15-20
years. The affected individual initially displays involuntary choreiform
movements, and as the disease develops these are accompanied by clumsi
ness, bradykinesia and the inability to sustain voluntary movement; later in
the course of the disease the abnormal movements often give way to a rigid,
akinetic state that leaves the patient wheelchair bound or even completely
immobile (Folstein, 1989). Although the diagnosis usually depends on the
appearance of overt neurological symptoms, these are almost always
preceded by subtle psychological abnormalities such as irritability and
personality changes, which in some cases can be the most disabling feature
of the condition (Hayden, 1981). Associated cognitive difficulties include
problems with memory and concentration, difficulty generating problem
solving strategies and profound slowing of mental activity. Anxiety and
depression are common features (Folstein et at., 1983a,b) and there is an
increased frequency of suicide compared with the general population
Molecular and Cell Biology of Neuropsychiatric Diseases
Edited by Frank Owen and Ruth Itzhaki
Published in 1994 by Chapman & Hall, London ISBN 0412 47800 5
1