Objective To develop an understanding of the molecular pathology of Huntington's disease (HD) and neurodegenerative diseases caused by CAG expansion thereby laying the ground work for the development of therapeutic strategies. This will involve the identification of the normal function of the huntingtin (htt) protein, the changes brought about by a CAG expansion, the generation of cellular and animal model systems of HD and the initiation of a parallel analysis of Machado Joseph disease (SCA3). A number of inherited, late onset, neurodegenerative disorders have been described which show anticipation when the respective gene is inherited through the male line. The neurodegeneration is selective, differs between the diseases and its biochemical basis is unknown. Isolation of the genes for five of these diseases: HD, SBMA, SCA1, DRPLA and MJD (SCA3) has shown the underlying mutation to be a CAG expansion. In all cases, the identification of the mutation has led to accurate diagnostic tests, and an understanding of the molecular basis of some of the genetic features, but it has done little to uncover the chain of events leading to the observed neuropathology. In all cases the repeat lies within the coding region and codes for a stretch of polyglutamine residues (polygln). It is particularly fascinating that these proteins can tolerate such a wide variation in the polygln size within the normal range, yet the further addition of a few residues causes the disease, and, that this apparently universal mutation, when present in different disease genes causes such strikingly selective cell death. An understanding of this process is central to the eventual design of methods to prevent or delay the onset or interrupt the progression of these diseases. We plan to carry out a comprehensive analysis of the molecular basis of HD and MJD. A unique set of complementary resources, in the form of antibodies and clones has already been generated by the partners. The normal function of huntingtin (htt), its cellular interactions and the mechanism by which the polyglutamine expansion changes this function must be established. In situ hybridisation, immunohistochemistry, immunoelectron microscopy and western analysis will be used to determine the cellular localisation of htt and SCA3 proteins and quantify their expression in normal and affected brains. An interspecies comparative sequence analysis of htt and its homologues will be used to identify functional domains. Htt will be expressed in vitro to allow the identification of interacting proteins. Cellular and animal models of HD will be developed using cDNA and genomic constructs carrying expansions, both to produce transgenic mice and for the introduction into neuronal cell lines. Such models are essential to study the disease mechanism and to allow the future testing of therapeutic agents that may block the progression of these devastating diseases for which there are no effective therapies. Fields of science natural sciencesbiological sciencesneurobiologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesphysical sciencesopticsmicroscopynatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesbasic medicinepathology Programme(s) FP4-BIOMED 2 - Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998 Topic(s) 3.4 - Genetic and immunological basis of neuromental diseases Call for proposal Data not available Funding Scheme CSC - Cost-sharing contracts Coordinator United Medical and Dental Schools of Guy's and St Thomas's Hospitals EU contribution No data Address 8th Floor Guy's Tower SE1 9RT London United Kingdom See on map Total cost No data Participants (4) Sort alphabetically Sort by EU Contribution Expand all Collapse all Centre National de la Recherche Scientifique France EU contribution No data Address 1,Rue Laurent Fries 67404 ILLKIRCH See on map Total cost No data Institut National de la Santé et de la Recherche Médicale France EU contribution No data Address 47,Boulevard de l'Hopital 75651 PARIS See on map Total cost No data MAX-PLANCK-GESELLSCHAFT ZUR FOERDERUNG DER WISSENSCHAFTEN E.V. Germany EU contribution No data Address Ihnestrasse 73 14195 BERLIN See on map Total cost No data Rijksuniversiteit Leiden Netherlands EU contribution No data Address 9503,P.O. Box 2300 RA LEIDEN See on map Total cost No data
