Dr Melanie Pritchard - Down Syndrome Research Laboratory

Monash University Department of Biochemistry and Molecular Biology Room 351, Bld 76, Clayton Phone:   +61 3 990 29221 Fax:        +61 3 9542 7199 Email:     Melanie.Pritchard@med.monash.edu.au

Research Interests

Neuropathology of Down syndrome
Development of mouse models of Down syndrome
Calcineurin signalling in neurones
Disrupted endocytosis in Down syndrome and Alzheimer's Disease 

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 due to developmental abnormalities of the brain. Individuals with DS have abnormalities in every system of the human body e.g. brain and heart defects, bone abnormalities, and immune system defects which makes them prone to infections. In addition, all individuals with DS develop Alzheimer's-like pathology by the age of 35. 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 have generated 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 and function. 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 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 the vesicles 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 diseasein both non-DS and Down syndrome individuals. This disturbance is characterised by the presence of enlarged endosomes. These enlarged endosomes are present long before the characteristic plaques of Alzheimer’s disease appear. We are currently exploring the biological function of Intersectin-1 in knockout mice with a view to understanding the potential contribution of this gene to the endocytic defects associated with DS and Alzheimer’s disease.

Representative Down syndrome Publications

Fuentes JJ, Pritchard MA, Planas AM, Bosch A, Ferrer I and Estivill X (1995) A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart. Hum. Mol. Genet. 4: 1935-1944.

Pucharcós C, Fuentes J-J, Casas C, de la Luna S, Alcantara S, Arbones ML, Soeiano E, Estivill X and Pritchard MA (1999) Alu-splice cloning of human Intersectin (ITSN), a putative multivalent binding protein expressed in proliferating and differentiating neurons and overexpressed in Down syndrome. Eur. J. Hum. Genet. 7: 704-712.

Dierssen M, Pritchard M, Fillat C, Arbones M, Aran J, Florez J and Estivill X (1999) Modelling Down syndrome in Mice. In Molecular-Genetic Techniques for Brain and Behaviour Research. Eds. W. Crusio and T. Gerlai. (Elsevier Science, Amsterdam) 13: 895-913.

Kola I and Pritchard M (1999) Animal models of Down syndrome. Mol. Med. Today 5: 276-277.

De Haan J, Susil B, Pritchard M and Kola I. (2003) An altered antioxidant balance occurs in Down syndrome fetal organs: implications for the “gene dosage effect” hypothesis. Neural Transm. 67: 67-83.

Keating DJ, Chen C and Pritchard MA. (2006) Alzheimer’s disease and endocytic dysfunction: clues from the Down syndrome-related genes, DSCR1 and Intersectin. Ageing Res. Rev. 5: 388-401.

Pritchard MA and Kola I. (2007) The biological bases of pharmacological therapies in Down syndrome. In: Therapies and Rehabilitation in Down syndrome. p18-28. Eds. JA Rondal, A Rasore-Quartino. Wiley Press

Keating DJ, Dubach D, Yu Y, Martin KR, Zhao YF, Chen C, Porta S, Arbonés ML, Mittaz L and Pritchard MA. (2008) DSCR1/RCAN1 regulates the exocytosis and fusion kinetics of large dense core vesicles in mouse chromaffin cells: implications for Down syndrome and Alzheimer’s disease. Hum. Mol. Genet. 17: 1020-1030.

Yu Y, Chu P, Bowser DN, Keating DJ, Dubach D, Harper I, Tkalcevic J, Finkelstein DI and Pritchard MA. (2008) Mice deficient for the chromosome 21 ortholog Itsn1 exhibit vesicle trafficking abnormalities. Hum. Mol. Genet. 17: 3281-390