Projects

Modelling molecular pathological events of Alzheimer's disease in zebrafish embryos

Our laboratory is currently involved in a number of projects investigating molecular pathological events associated with Alzheimer's disease. Our main focus is on the function of the presenilin genes (PSEN1 and PSEN2) that are the major loci for mutations causing Familial Alzheimer's Disease (FAD). Over 160 mutations causing FAD are known in the human PSEN1 gene and nearly all are mis-sense mutations that alter the protein coding sequence rather than non-sense mutations that truncate the protein. This led to the belief that truncated presenilin proteins have no function (i.e. they do not produce the dominant phenotype seen in FAD pedigrees). However, the unique characteristics of the zebrafish embryo model allowed us to discover that this is, in fact, not true. Instead, particular truncations of the presenilin proteins can be potently dominant negative in action. Using our unique assay for zebrafish psen2 activity (see below) we also discovered, surprisingly, that truncated PSEN1 proteins can inhibit the activity of PSEN2. We have now published this work (see Nornes et al. 2008). We believe our discovery may have implications for understanding the cause(s) of the sporadic (non-inherited) form of Alzheimer's disease that constitutes 95% of all Alzheimer's disease cases.

In other work we have discovered that, unlike in mice, the zebrafish PSEN2 orthologue, psen2, has essential developmental roles. In particular, changes in the activity of psen2, but not psen1, affect the development of a particular type of neuron in the developing spinal cord. This has given us a unique bioassay for psen2 activity. Our work is also shedding light on the central role of the presenilins in normal cell function and in cancer.

The Lardelli laboratory collaborates with a number of other laboratories in Adelaide to assist them with using zebrafish to further their reseach goals.