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Professor Pierre Drapeau: Entering the matrix of neurogenetic disorders--gene and drug discovery strategies with Zebrafish

Professor Pierre Drapeau, Ph.D.

Department of Pathology and Cell Biology

University of Montreal

Canada

The initial identification of mutations related to human disease often lacks biological validation of their pathogenic nature.  We have found that knockdown of the zebrafish homologues of several genes related to spinal cord diseases such as ALS resulted in abnormal motility and defects in motor neuron projections.  For several genes this abnormal phenotype could be rescued by over expression of native human mRNA but not by some of the disease-related alleles.  We are currently defining the network of interactions between these genes.  In addition we have generated inducible transgenic lines which we are using to screen small molecule libraries in search of compounds that can restore activity.  Finally, we have recently performed a large-scale genomic screen for mutations of several hundred synaptic genes in patients with developmental brain disorders, combined with biological validation in genetic model organisms.  We have identified over a dozen genes with de novo mutations (present in the patients but not in their parents) in cases of autism or schizophrenia.  Our results predict that as many as half the cases of these developmental disorders may be due to spontaneous (rather tan inherited) mutations.

We have validated some of these de novo mutations in zebrafish, including mutations of SHANK3 which we have identified in cases of schizophrenia, providing the first molecular genetic link between this disorder and the previously established role of SHANK3 in autism. 

Zebrafish thus provide a useful model for studying pathogenic nature of human brain disease-related alleles with potential for therapeutic discovery.

Date: Monday 23 August, 2010

Time: 12 noon – 1 pm (followed by refreshments)

Venue: MISCL Seminar room,

Level 3, Building 75

Monash University

Clayton campus

RSVP: lisa.hutton@monash.edu or nmh@med.monash.edu by Thursday 19 August, 2010