Down Syndrome Research Group

Pictured above from left to right - Kate Martin (Honours student), Renee Chehab (PhD student),Dr Melanie Pritchard, Yong Yu (visiting academic) and Daphne Dubach (PhD student)

Neurodegeneration in Down Syndrome

Down syndrome (DS) is the most common chromosomal abnormality found in humans - it occurs at a rate of 1 in 700 live births and is much more common than other genetic abnormalities. It is also the most common cause of intellectual disability in the community. Individuals with DS have abnormalities in every system of the human body e.g. brain defects, heart defects, leukaemia, bone abnormalities, Alzheimer’s disease, eye problems, and immune defects which make them prone to infections. Many of the problems experienced by people with DS also occur in the rest of the population - albeit at a lower rate and later in life. Individuals with DS have three copies of chromosome 21 instead of the normal two and therefore the functional characterisation of genes from chromosome 21 is crucial for understanding the cause of the disorder.

Our research focuses on the generation of mouse models of DS. We are generating transgenic mice, where the gene of interest is over-expressed to mimic the situation in DS, and knockout mice, in order to determine the normal biological function of the gene. We have identified two novel chromosome 21 genes, DSCR1 and Intersectin-1, which have the potential to contribute to neurodevelopmental and neurodegenerative aspects of the DS phenotype.
 
 DSCR1 negatively regulates the calcineurin pathway, a cellular pathway critical for brain development. DSCR1 has also been shown to be induced by oxidative stress and is up-regulated in Alzheimer’s disease. We have DSCR1 transgenic and knockout mice and are currently analysing their phenotype

Intersectin 1 Research Group

Pictured above from the left : Yong Yu (visiting trainee fellow), Dr Melanie Pritchard (CI) and Dr Po-yin Chu (postdoctoral fellow)

The role of Intersectin-1 in endocytic anomalies: implications for Down syndrome and Alzheimer's disease.

Individuals with Down syndrome have three copies of human chromosome 21, rather than the normal two. We have discovered a gene called Intersectin-1, located on human chromosome 21,  that is expressed at higher levels than normal in individuals with Down syndrome. Intersectin-1 has a role in endocytosis, a process whereby cells take up molecules from the outside. Endocytosis occurs in all cells but is highly specialised in the brain where chemical transmitters are released and then rapidly recovered by endocytosis in a process enabling neurones to pass signals to one another. A disturbance in endocytosis has been reported as the earliest hallmark of Alzheimer’s disease in both non-Down syndrome and Down syndrome individuals. This disturbance is characterised by the presence of enlarged endosomes (small packages in neuronal cells containing chemical neurotransmitters formed during endocytosis). These enlarged endosomes are present long before the characteristic plaques of Alzheimer’s disease appear. Since all individuals with Down syndrome develop Alzheimer’s-like neuropathology, there must be a common disease mechanism that can be traced to the extra gene dosage from chromosome 21. We propose that a malfunctioning of Intersectin-1 is this common mechanism and we aim to test our hypothesis by the generation and analysis of mouse models of disrupted endocytosis.