Omic Studies of Neurodegenerative Disease - Part A

1. Auflage 2015
ISBN: 978-0-12-801621-3
Verlag: Academic Press
Format: EPUB
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, Band 121, 214 Seiten, Format (B × H): 152 mm x 229 mm

Reihe: International Review of Neurobiology

Omic Studies of Neurodegenerative Disease: Part A is part of a well-established international series on neuroscience that examines major areas of basic and clinical research, along with emerging and promising subfields.

The book informs the reader on the current state of the studies used to evaluate the mechanisms, causes, and treatment of neurodegeneration through a combination of literature reviews and examples of current research.



- Provides the expertise of leading contributors in the field
- Demonstrates how findings in the fields of genomics, proteomics, and metabolomic studies can combined for further insights
- Informs the reader on the current state of the studies used to study the mechanisms, causes, and treatment of neurodegeneration through a combination of literature reviews and examples of current research

Zielgruppe

<p>The volume will appeal to a wide audience including students and researchers from across the life science community, particularly those interested in neuroscience.</p>

Autoren/Hrsg.

Weitere Mitwirkende

Hurley, Michael J.

Fachgebiete

• Medizin | Veterinärmedizin Medizin | Public Health | Pharmazie | Zahnmedizin Klinische und Innere Medizin Neurologie, Klinische Neurowissenschaft
• Naturwissenschaften Biowissenschaften Biowissenschaften Neurobiologie, Verhaltensbiologie
• Naturwissenschaften Biowissenschaften Entwicklungsbiologie
• Interdisziplinäres Wissenschaften Wissenschaften Interdisziplinär Neurowissenschaften, Kognitionswissenschaft

Inhaltsverzeichnis

- Alzheimer's Disease: Genomics and Beyond

Fuhai Song, Guangchun Han, Zhouxian Bai, Xing Peng, Jiajia Wang and Hongxing Lei

- The Potential of Proteomics in Understanding Neurodegeneration

Ramavati Pal, Jan Petter Larsen and Simon Geir Moller

- Proteomics Approach to Identify Biomarkers in Neurodegenerative Diseases

Annapurna Nayak, Gregory Salt, Sunil K. Verma and Uday Kishore

- Uncovering Neurodegenerative Protein Modifications Via Proteomic Profiling

Xavier Gallart-Palau, Aida Serra and Siu Kwan Sze

- Comparative Proteomics for the Evaluation of Proteins Expression and Modifications in Neurodegenerative Diseases

Antonio Conti and Massimo Alessio

Leseproben

Chapter One Alzheimer's Disease
Genomics and Beyond
Fuhai Song*,†; Guangchun Han*; Zhouxian Bai*,†; Xing Peng*,†; Jiajia Wang*,†; Hongxing Lei*,‡,1    * CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, PR China
† University of Chinese Academy of Sciences, Beijing, PR China
‡ Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing, PR China
1 Corresponding author: email address: [e-mail] Abstract
Alzheimer's disease (AD) is a major form of senile dementia. Despite the critical roles of Aß and tau in AD pathology, drugs targeting Aß or tau have so far reached limited success. The advent of genomic technologies has made it possible to gain a more complete picture regarding the molecular network underlying the disease progression which may lead to discoveries of novel treatment targets. In this review, we will discuss recent progresses in AD research focusing on genome, transcriptome, epigenome, and related subjects. Advancements have been made in the finding of novel genetic risk factors, new hypothesis for disease mechanism, candidate biomarkers for early diagnosis, and potential drug targets. As an integration effort, we have curated relevant data in a database named AlzBase. Keywords Brain transcriptome Genome-wide association study Whole-exome sequencing Epigenome profiling Biomarker 1 Introduction
Alzheimer's disease (AD) affects a large population in the senior community, likely 10 million in China alone (Han et al., 2014; Lei, 2010). The pathological hallmarks of AD include extracellular deposit of Aß amyloid plaques derived from APP and intraneuronal neurofibrillary tangles (NFTs) from hyperphosphorylation of tau. Much of the efforts in AD research have been devoted to molecular pathways centered at Aß or tau. The vast majority of novel treatment strategies are also targeting either Aß or tau. Nevertheless, promising results from animal models have not translated well in human clinical trials (Callaway, 2012). Thus, revolutionary ideas outside of the hallmarks are desperately needed. Technology developments in genomics have provided a variety of tools to investigate AD at the whole system level (Fig. 1). Earlier genetic linkage or association studies in both early-onset AD (EOAD) and late-onset AD (LOAD) have gradually evolved into genome-wide association studies (GWASs) and more recently developed into whole-exome sequencing (WES) and whole-genome sequencing (WGS; Bettens, Sleegers, & Van Broeckhoven, 2013; Guerreiro, Bras, & Hardy, 2013). Transcriptome studies are still in the process of transiting from microarray to RNA-seq (Sekar et al., 2015). Several types of epigenetic and epigenomic studies have been conducted on AD, including DNA methylation, histone modification, and microRNA (Lunnon & Mill, 2013). As a valuable supplement to the traditional studies on human subjects and animal models, induced pluripotency stem cell (iPSC) technology has been increasingly used to bridge the gap in translational medicine (Israel et al., 2012). In this review, we will survey representative investigations applying genomics technologies to the study of AD and relevant processes such as aging and neurological disorders. Figure 1 A framework of key factors and events in AD pathogenesis. 2 GWASs on the Primary Phenotype of AD
The quality of GWASs depends heavily on the sample size. In the most recent large-scale GWAS of AD (Lambert et al., 2013), over 74K samples were included in the meta-analysis (all of European ancestry), including ~ 54K samples in stage 1 (previously published datasets) and ~ 20K samples in stage 2 (new datasets). Over 7M imputed single-nucleotide polymorphisms (SNPs) were used in the meta-analysis of stage 1 datasets. In stage 2, only SNPs showing moderate significance in stage 1 (P < 1 × 10- 3) were genotyped (~ 11K SNPs). In the meta-analysis of stage 1 datasets, the significance of APOE and nine other previously identified genes was confirmed (Table 1), including CR1, BIN1, CLU, PICALM, ABCA7, CD2AP, EPHA1, MS4A4E, and CD33. Additionally, five new loci reached genome-wide significance in the discovery datasets, namely, SORL1, PTK2B, DSG2, HLA-DRB5, and SLC24A4. When combining the discovery and replication datasets, seven new loci reached genome-wide significance, including INPP5D, MEF2C, NME8, FERMT2, ZCWPW1, CELF1, and CASS4. Among these 22 loci, CD33 and DSG2 did not reach genome-wide significance in the combined datasets. These genes are involved in immune response, lipid metabolism, synaptic function, and Aß/tau-related pathways. Table 1 Key Genes from Genetic Studies of Late-Onset AD CR1 Complement component (3b/4b) receptor 1 (Knops blood group) Complement pathway; clearance of amyloid BIN1 Bridging integrator 1 Synaptic vesicle endocytosis CLU Clusterin Stress response; lipid metabolism PICALM Phosphatidylinositol-binding clathrin assembly protein Synaptic vesicle; lipid metabolism ABCA7 ATP-binding cassette, subfamily A (ABC1), member 7 Lipid metabolism; immune CD2AP CD2-associated protein Regulation of actin cytoskeleton; endocytosis EPHA1 EPH receptor A1 Signaling in nervous system development; immune MS4A4E Membrane-spanning four domains, subfamily A, member 4E Immune; signaling CD33 CD33 molecule Immune; signaling SORL1 Sortilin-related receptor, L(DLR class) A repeats containing Endocytosis and sorting PTK2B Protein tyrosine kinase 2 beta Synaptic transmission DSG2 Desmoglein 2 Cell adhesion HLA-DRB5 Major histocompatibility complex, class II, DR beta 5 Immune response SLC24A4 Solute carrier family 24 (sodium/potassium/calcium exchanger), member 4 Ion transport INPP5D Inositol polyphosphate-5-phosphatase, 145 kDa Blood cell; immune MEF2C Myocyte enhancer factor 2C Transcription regulation; brain development NME8 NME/NM23 family member 8 Cytoskeleton FERMT2 Fermitin family member 2 Cell–matrix adhesion ZCWPW1 Zinc finger, CW type with PWWP domain 1 Epigenetic regulation; blood trait CELF1 CUGBP, Elav-like family member 1 mRNA processing; cytoskeleton CASS4 Cas scaffolding protein family member 4 Cell adhesion; signaling TP53INP1 Tumor protein p53-inducible nuclear protein 1 Autophagic cell death IGHV1-67 Immunoglobulin heavy variable 1–67 (pseudogene) Immune response PDE1A Phosphodiesterase 1A, calmodulin dependent Calcium signaling RYR3 Ryanodine receptor 3 Calcium signaling Besides testing the significance at the SNP level, gene-level test may reveal new genes affecting AD susceptibility. In a follow-up work of the above-described study (Escott-Price et al., 2014), gene-level analysis identified two genes with no previous reports, TP53INP1 and IGHV1-67. The three most significant SNPs in TP53INP1 represented at least two partially independent signals, while the two most significant SNPs in IGHV1-67 represented the same signal. As for the gene function, TP53INP1 is involved in apoptosis and IGHV1-67 is involved in immune response. We have adopted a different strategy in our reanalysis of public GWAS datasets. We...

Über Autor(innen)

Hurley, Michael J.
Michael Hurley has 20 years of experience conducting research in to the cause and consequence of neurodegeneration in brain. He currently works at Imperial College London.