Worm Breeder's Gazette 15(4): 19 (October 1, 1998)
These abstracts should not be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of the author.
|1||Department of Human Genetics, Sylvius Laboratory, Leiden University Medical Center, Leiden, The Netherlands|
|2||The Netherlands Cancer Institute, Division of Molecular Biology, Amsterdam.|
Huntington's disease (HD) is a neurodegenerative CAG (gln) repeat expansion disorder with a mid-life onset. Animal models may assist in the understanding of the molecular pathology of HD and other neurodegenerative diseases caused by similar repeat expansions. In mice an expanded CAG repeat in exon 1 of the HD gene is sufficient to cause a progressive neurological phenotype. Thus far no HD homolog has been identified in C. elegans. We have generated transgenic nematodes carrying exon 1 or exon 1 to 7 of the human HD gene, with 17, 73 or 140 CAG repeats. The transgenes are present either as an extrachromosomal array or integrated into the genome. Expression of the transgenes is driven by the HSP promoter which is regulated by heatshock. The 17, 73 and the 140 CAG repeats are stable upon transmission to offspring in C. elegans whereas they are unstable in mammals. After heat shock induction HD expression of the transgenes can be detected. Expression of the 140 HD transgene could only be detected with a monoclonal antibody which specifically recognises expanded glutamine repeats and with a polyclonal antibody. The protein encompassing the expanded glutamine repeat is more stable in time than the protein containing the normal repeat. An extensive survey of transgenic worms containing the transgenes revealed that a single heat shock of either eggs or L1 larvae has no significant effect on viability. Analysis of the nematodes after recurrent heat shocks under different environmental conditions is ongoing, including studies in which specific neurons are stained with fluorescent dyes such as DiO. Preliminary results indicate that in one line expressing exon 1 with an expanded repeat dye-filling of the phasmid neurons is affected. Interestingly, we have also identified an endogenous C. elegans protein which reacts with the monoclonal antibody against expanded glutamine repeats. A further characterisation of this protein, which might carry an expanded glutamine repeat, is underway.