| Abstract No.: | B-C2124 |
| Country: | Canada |
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| Title: | ATTENUATED GROUP I MGLUR SIGNALING IN PRESYMPTOMATIC HUNTINGTON’S DISEASE MOUSE MODEL |
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| Authors/Affiliations: | 1 Maryse Paquet*; 1 Fabiola M. Ribeiro; 1 Lucimar T. Ferreira; 1 Tamara Cregan; 1 Stephen S. Ferguson;
1 Robarts Research Inst./UWO, London, ON, Canada
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| Content: | Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a mutated protein called huntingtin (Htt), which presents a polyglutamine expansion in its amino-terminal region. Glutamate, the major excitatory neurotransmitter in the brain, has been postulated to play an important role in the pathogenesis and excitotoxic neuronal cell loss in the striatum and neocortex of HD patients. We have recently shown that optineurin, an Htt-interacting protein, interacts with group I metabotropic glutamate receptors (mGluR1 & mGluR5) to attenuate their agonist-induced signaling in cell cultures (Anborgh et al. 2005). Objectives: Examine group I mGluR signaling in wild-type (HdhQ20/Q20) and mutant (HdhQ111/Q111) Htt knock-in mice throughout the early progression of the pathology. Materials and methods: Basal and agonist (DHPG)-induced IP3 signaling was assessed with inositol phosphate (InsP) formation assay using [3H]-inositol incorporation in acute striatal slices from five age groups: 0-1, 2-3. 6-7, 8-9, and 11-14 months of HdhQ20/Q20 and HdhQ111/Q111 Htt knock-in mice (Jackson Laboratory). Western blotting experiments were performed on striatal brain lysates to examine changes in the expression of mGluR1a (1:1,000 Upstate Biotechnology), mGluR5 (1:4,000 Upstate Biotechnology), optineurin (1: 1,000 Cayman Chemical Company), and Htt (1:1,000 Chemicon) proteins, normalized to actin levels (1:10,000 Sigma). Cell surface expression of mGluR5 was also assessed by biotinylation experiments using acute striatal slices. Results: Compared to the DHPG-induced IP3 signaling of age matched HdhQ20/Q20, group I mGluR signaling in the striatum of HdhQ111/Q111 mice was attenuated. This difference was significant for mice up to 10 months old, whereas no difference was observed in the striatum of 11 to 14 months old mice. In contrast, basal InsP formation was unchanged across genotypes and mouse ages. This attenuated group I mGluR signaling in HdhQ111/Q111 striatum was not due to a decrease in protein expressions of the two receptors, mGluR1a and mGluR5, optineurin, or Htt proteins. Preliminary experiments suggest that there is no difference in basal cell surface expression of the mGluR5 receptors between striatum of wild-type and mutant Htt knock-in mice. Thus, mutant Htt protein does not modify signaling by disturbing cell surface trafficking of the receptor. We are currently investigating if the mutant Htt protein affects group I receptor coupling to Gq or its downstream signaling patways. Conclusion: Group I mGluR signaling is compromised in early stages of the HD pathology in HdhQ111/Q111 Htt knock-in mice. |
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