Molecular Biology of Neuropsychiatric Disorders (Nucleic Acids and Molecular Biology, 23)

303 Pages·2008·5.02 MB·English

by  Dieter B. Wildenauer

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Institut für Biochemie
Biozentrum
Am Hubland
97074 Würzburg
Germany
Dieter B. Wildenauer (Ed.)
Molecular Biology
of Neuropsychiatric
Disorders
With 15 Figures and 8 Tables
(cid:2)(cid:0)(cid:4)
Editor
Dieter B. Wildenauer
Graylands Hospital
Center for Clinical Research in Neuropsychiatry (CCRN)
Claremont WA 6910
Australia
ISBN 978-3-540-85382-4 e-ISBN 978-3-540-85383-1
ISSN 0933-1891
Library of Congress Control Number: 2008933566
© 2009 Springer-Verlag Berlin Heidelberg
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Preface
The intention of this book is to give an overview about ongoing research into molecular
causes for disorders that affect the human brain. These disorders afflict mainly human
behavior and are, since borders between “normal” and “abnormal” behaviors are
continuous and hard to define, not always easy to diagnose. We have included the
major psychoses (schizophrenia and affective disorders), autism, attention deficit
hyperactivity, and anxiety disorders, as well as addictive and suicidal behavior.
Neuropathological alterations in these disorders are usually not detectable or restricted
to sporadic cases and, if present, not easy to define as causative. In contrast, patho-
logical alterations in the brain are present in the two included neuropsychiatric disor-
ders, Alzheimer’s and Parkinson’s disease. Detection of pathological abnormalities
has been helpful as a starting point for studies of the biochemistry and molecular
biology of these diseases. Our goal was to describe current research directions using
new methods and information provided by molecular biology and molecular genetics.
We have included selected, but in our opinion (and therefore biased) most promising,
findings rather than attempting to give a complete overview of findings in these
disorders. Given the large number of publications appearing each month in the field
(up to 50 in one month as estimated from the PubMed entry) it is almost certain that
the book would be already out of date while still in print. Specific databases that col-
lect all new information on websites accessible to the public are superior and already
available for schizophrenia (http://www.schizophreniaforum.org/res/sczgene/default.
asp), Alzheimer’s disease (http://www.alzforum.org/res/com/gen/alzgene/default.
asp), and Parkinson’s disease (http://www.pdgene.org/).
The complex nature of psychiatric disorders with many factors contributing to
susceptibility, but not always necessary for expression of the disease, renders the
identification of molecular causes extremely difficult. Whilst causes for the two
neurodegenerative disorders, Alzheimer’s and Parkinson’s disease, have been
uncovered and their molecular biology is being studied, the search for causes for
other neuropsychiatric disorders has not yet led to convincing findings. Complexity
and variation in phenotype are major obstacles for these studies. In particular, the
difficulty of phenotype definition makes it is hard to establish identical samples for
replication or confirmation of findings. As a consequence, most of the published
findings are not easy to prove or disprove and may just add to the flood of unconfirmed
positive findings in the field. Nevertheless, we are optimistic that a continuing collection
v
vi Preface
of data will be of help in the discovery of the molecular connections and pathways
that play a critical role in the development of these disorders.
Finally, I wish to thank all contributors to this book, as well as Professor Dr.
Hans J. Gross for encouragement and Frau Gramm from Springer Verlag for help
in submission for publication.
Perth Dieter B. Wildenauer
June 2008
Contents
Decoding the Genetics and Underlying Mechanisms
of Mood Disorders ............................................................................................ 1
Sevilla D. Detera-Wadleigh and Takeo Yoshikawa
1 Introduction .................................................................................................... 2
2 Bipolar Disorder ............................................................................................. 5
2.1 Clinical Presentation and Epidemiology .............................................. 5
2.2 Genetic Analysis ................................................................................... 6
2.3 Alternative and Complementary Strategies .......................................... 15
3 Depression ...................................................................................................... 24
3.1 Clinical Presentation and Epidemiology .............................................. 24
3.2 Genetic Analysis of Depression ............................................................ 25
3.3 Therapeutics and Associated Mechanisms; Pharmacogenetics ............ 27
3.4 Neurogenesis ......................................................................................... 29
3.5 The Endocrine System (hypothalamic-pituitary-adrenal
(HPA) axis) .......................................................................................... 31
3.6 Animal Studies ...................................................................................... 33
3.7 Postmortem Brain Studies .................................................................... 36
4 Perspectives ......................................................................................................................... 37
References .......................................................................................................... 38
Dissecting the Molecular Causes of Schizophrenia ...................................... 51
Dieter B. Wildenauer, Diah Mutiara B. Wildenauer,
and Sibylle G. Schwab
1 Introduction ................................................................................................ 52
2 Diagnosis .................................................................................................... 52
3 Therapy ...................................................................................................... 52
4 Incidence, Prevalence ................................................................................. 53
5 The Search for Biological Causes ............................................................. 53
6 Epidemiology ............................................................................................. 54
7 Neuropathology .......................................................................................... 56
8 Neurotransmitter Hypotheses .................................................................... 57
vii
viii Contents
9 Molecular Genetics .................................................................................... 58
9.1 Localization of Susceptibility Genes
by Linkage Analysis ....................................................................... 58
9.2 Genetic Association........................................................................ 59
10 Gene Expression ........................................................................................ 69
10.1 mRNA Expression .......................................................................... 70
10.2 miRNA ........................................................................................... 70
10.3 Protein Expression.......................................................................... 71
10.4 Epigenetics ..................................................................................... 71
11 Animal Models .......................................................................................... 72
12 Conclusion ................................................................................................. 73
References .......................................................................................................... 73
Autism Spectrum Disorders ............................................................................ 81
Sabine M Klauck
1 Introduction ............................................................................................... 81
2 Molecular Genetic Screening.................................................................... 84
2.1 Genome-Wide Screens and Fine-Mapping
Approaches ....................................................................................... 84
2.2 Chromosomal Aberrations ................................................................ 88
2.3 Candidate Genes ............................................................................... 89
3 Future Directions ...................................................................................... 91
References .......................................................................................................... 92
Molecular Genetics of ADHD ........................................................................ 99
Virginia L. Misener and Cathy L. Barr
1 Complexities of the ADHD Phenotype .................................................... 100
1.1 Developmental Shifts ........................................................................ 101
1.2 Gender Effects .................................................................................. 102
2 Genetic Basis of ADHD ........................................................................... 104
3 Environmental Risk Factors ...................................................................... 105
4 Molecular Approaches to Gene Identification .......................................... 106
4.1 Candidate Gene Studies in ADHD ................................................... 107
4.2 Molecular Genetic Studies Using Population-Based
Samples ............................................................................................. 130
4.3 Genome Scans for ADHD ................................................................ 131
5 Relationship of the Molecular Genetic Findings in ADHD
to Reading Disabilities .............................................................................. 133
6 Interpretation of the Molecular Genetic Studies ...................................... 135
7 After the Linkage or Association Finding ................................................ 135
8 Implications of the Molecular Genetic Findings for Diagnosis
and Treatment ........................................................................................... 138
References ....................................................................................................... 139
Contents ix
The Genetics of Anxiety Disorders ............................................................... 165
Steven P. Hamilton
1 Anxiety Disorders ..................................................................................... 165
2 Panic Disorder ........................................................................................... 166
3 Phobias ...................................................................................................... 169
4 Generalized Anxiety Disorder .................................................................. 170
5 Obsessive Compulsive Disorder ............................................................... 171
6 Genetic Analysis of Anxious Personality Traits ....................................... 174
7 Conclusion ................................................................................................ 175
References ....................................................................................................... 176
Molecular Biology of Addiction and Substance Dependence ..................... 187
Sibylle G Schwab, Adrian Scott, and Dieter B Wildenauer
1 Introduction ............................................................................................... 188
2 Heritability of Substance Dependence...................................................... 188
3 Biology of Drug-Induced Changes in the Brain ....................................... 191
4 Molecular Genetic Evidence of Substance Dependence .......................... 193
4.1 Heroin ............................................................................................... 194
4.2 Nicotine ............................................................................................. 196
4.3 Alcohol ............................................................................................. 198
5 Conclusion ................................................................................................ 199
References ....................................................................................................... 199
Neurobiology of Suicide.................................................................................. 205
Brigitta Bondy and Peter Zill
1 Introduction ............................................................................................... 206
2 The Clinical Phenotype ............................................................................. 206
2.1 The Link Between Mental Morbidity and Suicide ........................... 207
3 Pathophysiological Mechanisms ............................................................... 208
3.1 The Neurochemical Basis of Suicidality .......................................... 208
3.2 Genetic Contribution to Suicidal Behavior ...................................... 213
3.3 Suicide as Interplay of Genes and Environment .............................. 219
4 Conclusions ............................................................................................... 220
References ....................................................................................................... 221
Molecular Genetics of Alzheimer’s Disease ................................................. 229
Giuseppe Verdile and Ralph N. Martins
1 Introduction ............................................................................................... 230
2 Familial Alzheimer’s Disease ................................................................... 230
2.1 The Amyloid Precursor Protein (APP) Gene ................................... 231
2.2 The Presenilin Genes ........................................................................ 239
3 Apolipoprotein E (APOE ε4): Strongest Genetic Risk Factor
for Sporadic AD ........................................................................................ 246
x Contents
3.1 The Apolipoprotein e4 Allele ........................................................... 246
3.2 Apolipoprotein E (ApoE) and Its Role in AD .................................. 250
3.3 Mechanisms by Which ApoE May Contribute to AD ..................... 252
4 Other Genetic Risk Factors ....................................................................... 254
5 Concluding Remarks ................................................................................. 257
References ....................................................................................................... 257
Molecular Biology of Parkinson’s Disease ................................................... 277
Abbas Parsian and Biswanath Patra
1 Introduction ............................................................................................... 278
2 Molecular Mechanisms in the Development
of Parkinson’s Disease .............................................................................. 279
2.1 The Role of Iron and Oxidative Stress ............................................. 279
2.2 Role of Alpha-Synuclein .................................................................. 280
2.3 Mitochondrial Polymorphism and Deletions
in Parkinson’s Disease ...................................................................... 282
2.4 Heat Shock Protein Chaperone (HSC-70) ........................................ 283
2.5 Dopamine Neurotransmission and Metabolism ............................... 283
2.6 Association of LRRK2 Gene and Inappropriate
Phosphorylation in Parkinson’s Disease ........................................... 284
2.7 Role of Glutathione-S-Transferase Gene
in the Development of Parkinson’s Disease ..................................... 285
3 Conclusions ............................................................................................... 285
References ....................................................................................................... 286
Index ................................................................................................................. 291