Genetic risk factors for neurodegenerative diseases and their role in the regulation of regional gene expression in the
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
Some of the most common and devastating neurological conditions, including Parkinson‘s and Alzheimer‘s disease, are caused by specific nerve cells in the brain gradually dying. At the moment little is known about why this happens and we cannot stop the process.
Recently neuroscientists have been able to show that some individuals inherit risk factors in their DNA, which make them more likely to develop these neurodegenerative conditions. However, we do not know how these risk factors change the way nerve cells behave or make these cells more vulnerable.
The aim of our work is to investigate how inherited risk factors influence gene expression so that we can understand what types of nerve cell functions change and why the cells die. In order to do this we will use new microarray technologies to obtain detailed genetic and gene expression information about human brain tissue. By understanding how inherited risk factors influence gene expression we hope we can find treatments capable of protecting nerve cells within the brain and so halt the progression of neurodegenerative diseases like Parkinson‘s and Alzheimer‘s disease.
Recently neuroscientists have been able to show that some individuals inherit risk factors in their DNA, which make them more likely to develop these neurodegenerative conditions. However, we do not know how these risk factors change the way nerve cells behave or make these cells more vulnerable.
The aim of our work is to investigate how inherited risk factors influence gene expression so that we can understand what types of nerve cell functions change and why the cells die. In order to do this we will use new microarray technologies to obtain detailed genetic and gene expression information about human brain tissue. By understanding how inherited risk factors influence gene expression we hope we can find treatments capable of protecting nerve cells within the brain and so halt the progression of neurodegenerative diseases like Parkinson‘s and Alzheimer‘s disease.
Technical Summary
Neurodegenerative diseases, such as Parkinson‘s and Alzheimer‘s disease, are amongst the most common and devastating neurological conditions. Using whole genome SNP arrays amazing progress has been made in our understanding of the genetic risk factors contributing to the sporadic forms of these conditions. However, since the vast majority of reported risk-associated SNPs are not within coding regions, the identification of these genetic risk factors has not automatically led to a clear understanding of the underlying pathophysiology of neurodegenerative disease.
The biological aim of this study is to fill this gap in our knowledge by identifying SNPs that not only increase an individual‘s risk of developing a neurodegenerative disease, but also change gene expression in the human brain. In support of this research approach, Myers and colleagues demonstrated that high quality gene expression data can be generated from post-mortem brain tissue and that SNP genotypes can be correlated to gene expression levels. Thus, by developing a deeper understanding of the heritability of gene expression within the human brain it should be possible to link genetic risk factors with genes and signalling systems, and so begin to generate new much-needed treatment strategies.
Since risk-associated SNPs are present in the normal population as well as the disease population, using control brain tissue we can study their downstream affects on gene expression without the complications of neuronal death, glial response and symptomatic treatments. We intend to use post-mortem control human brain tissue to collect samples from well-defined brain regions, known to be particularly affected in the most common neurodegenerative diseases. Examples include, the substantia nigra, the site of predominant dopaminergic neuron loss in Parkinson‘s disease.
Using microarray technology, we will rapidly produce large quantities of high quality, genome-wide paired SNP and exon-specific expression data. This information will be stored in a publicly accessible database that can be queried by brain region, SNP or gene transcript. In this way, we hope to generate a resource that will not only be useful for our own research into neurodegenerative diseases, but for those studying other neurological conditions. In our case, the data analysis will be focused on identifying downstream gene expression changes associated with individual SNPs known to increase the risk of developing a neurodegenerative disease.
Thus, we hope to bridge the gap between genetic risk and pathophysiology. In this way, we may be able to provide new therapeutic strategies for the early and effective treatment of neurodegenerative diseases.
The biological aim of this study is to fill this gap in our knowledge by identifying SNPs that not only increase an individual‘s risk of developing a neurodegenerative disease, but also change gene expression in the human brain. In support of this research approach, Myers and colleagues demonstrated that high quality gene expression data can be generated from post-mortem brain tissue and that SNP genotypes can be correlated to gene expression levels. Thus, by developing a deeper understanding of the heritability of gene expression within the human brain it should be possible to link genetic risk factors with genes and signalling systems, and so begin to generate new much-needed treatment strategies.
Since risk-associated SNPs are present in the normal population as well as the disease population, using control brain tissue we can study their downstream affects on gene expression without the complications of neuronal death, glial response and symptomatic treatments. We intend to use post-mortem control human brain tissue to collect samples from well-defined brain regions, known to be particularly affected in the most common neurodegenerative diseases. Examples include, the substantia nigra, the site of predominant dopaminergic neuron loss in Parkinson‘s disease.
Using microarray technology, we will rapidly produce large quantities of high quality, genome-wide paired SNP and exon-specific expression data. This information will be stored in a publicly accessible database that can be queried by brain region, SNP or gene transcript. In this way, we hope to generate a resource that will not only be useful for our own research into neurodegenerative diseases, but for those studying other neurological conditions. In our case, the data analysis will be focused on identifying downstream gene expression changes associated with individual SNPs known to increase the risk of developing a neurodegenerative disease.
Thus, we hope to bridge the gap between genetic risk and pathophysiology. In this way, we may be able to provide new therapeutic strategies for the early and effective treatment of neurodegenerative diseases.