Alzheimer’s Disease Genetics Laboratory
Alzheimer’s Disease Genetics Laboratory
You can read about our research on Alzheimer's disease and watch video tours through our laboratory etc. by visiting the online article, "Reeling in Alzheimer's Disease".
Mutations in the two PRESENILIN genes, PSEN1 and PSEN2, cause the majority of inherited Alzheimers disease. These two genes encode two very similar proteins that appear to control a number of different signaling pathways in cells. The best understood function of PRESENILIN proteins is in cleavage of transmembrane proteins within lipid bilayers. This leads to the release of the intracellular domains of signal receptor proteins such as NOTCH and the AMYLOID BETA A4 PRECURSOR PROTEIN (APP). These intracellular domains then enter the nucleus to regulate gene activity. Presenilins also appear to be important for the process of autophagy, "self-eating" in which cells break down and recycle protein aggregates and their own organelles. Despite intensive research, there is still no general agreement about the pathological effects of mutations in PSEN1 and PSEN2. Many people think that it is the effect of these mutations on APP cleavage that is critical but others argue that effects on autophagy may, instead, be the key to understanding Alzheimer's disease.
Our laboratory uses a number of techniques to analyse the functions of the PRESENILIN genes as well as other genes involved in Alzheimer's disease such as APP and SORL1. We have developed unique in vivo assays for analysis of APP protein cleavage (i.e. "gamma-secretase activity") and for measurement of autophagy. We are also using the latest genome engineering techiques to introduce human Alzheimer's disease mutations into our experimental model, the zebrafish (see below). We then study these mutant zebrafish using "deep sequencing" analysis of gene expression to observe how the mutations change the molecular state of cells in their brains. This work involves sophisticated bioinformatic analysis of changes in gene expression.
Zebrafish are small, freshwater fish originating from India that are commonly kept in home aquaria. However, most people are unaware that this fish is also used as a powerful model system for studying how genes control the embryonic development of vertebrates including humans.
Zebrafish have particular characteristics that make them very suitable for genetic research on embryo development. This has led to an explosion of interest in zebrafish research in the last 20 years. Zebrafish embryos develop extremely rapidly - from the one cell stage to hatching of the tiny fish takes only 48 hours. The embryos are also completely transparent allowing us to see every cell in the embryo and to follow its fate. There are techniques that can show where genes are active in particular cells of whole embryos. The relatively large size of zebrafish eggs (compared to mouse eggs for example) makes it very easy to inject DNA to produce transgenic zebrafish. Female zebrafish release large numbers of eggs and this allows us to examine genetic phenomena with great statistical accuracy. Hundreds of mutations have been found that affect embryo development and these are now being investigated intensively in many laboratories around the world. It has also recently become possible to engineer desired mutations into the zebrafish genome allowing us to accurately model human genetic diseases. The fact that zebrafish embryos are vertebrates, small, numerous and develop externally is making them increasingly popular with the biomedical industry for screening for drugs to treat human disease.
Zebrafish have an amazing ability to regenerate their tissues after damage and this includes their brain and spinal cord. So it is doubtful that they will ever be a good model of Alzheimer's disease at the tissue level. However, because zebrafish possess most of the same genes that humans possess they can be used to analyse the effects of molecular changes in Alzheimer's disease at the sub-cellular level. For example, we can change the expression or function of genes known to be invovled in Alzheimer's disease and observe how this alters the expression and function of other genes and proteins.