| Abstract No.: | C-C3120 |
| Country: | Canada |
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| Title: | DELETION OF THE PALMITOYL TRANSFERASE HIP14 RESULTS IN A HUNTINGTON DISEASE LIKE PHENOTYPE IN MICE |
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| Authors/Affiliations: | 1 Roshni Singaraja*; 1 Austen Milnerwood; 1 Kun Huang; 1 Rochelle Hines; 1 Shaun Sanders; 1 Kuljeet Vaid; 1 Fiona Young; 1 Lynn Raymond; 1 Alaa El-Husseini;
1 University of British Columbia, Vancouver, BC, Canada
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| Content: | Objectives: HIP14 (ZDHHC17) is a mammalian palmitoyl transferase that interacts robustly with wild-type huntingtin (htt), but has significantly reduced interaction with mutant polyglutamine expanded htt. As a result, the palmitoylation of mutant htt is significantly reduced. If altered palmitoylation of mutant htt by HIP14 is crucial in the pathogenesis of HD, HIP14-/- mice might be expected to display a phenotype similar to HD.
Materials and Methods: HIP14-/- mice were generated using targeted embryonic cells. Neuropathological analysis using MRI and stereology were performed, as were behavioural analyses using rotorod, open field and straight line swim tests. Standard electrophysiological assessments, electron microscopical analyses and biochemical palmitoylation assays were also used to characterize these mice.
Results: Analysis of HIP14-/- mice yielded many features that were similar to the HD phenotype in YAC128 htt transgenic mice. These included a significant decrease in striatal volume (wt:13.5±0.7, HIP14-/-:11.2±0.8 mm3, n=7, p=0.0002) and decreases in striatal neuronal counts (wt:17.9±1.8x105, HIP14-/-:16.2±1.2 x105, n=11, p=0.01) and size (wt:80.2±4.8, HIP14-/-:59.6±3.8 µm3, n=7, p=0.02). In addition, HIP14-/- mice were defective in tests of motor co-ordination such as fixed (wt:60±0, HIP14-/-:46.5±22.4, sec, n=6, p=0.009) and accelerating rotarod (wt:290.9±27.2, HIP14-/-:265.9±78.7, sec, n=13, p=0.03) and swim speed (wt:2.7±0.6, HIP14-/-:3.2±1.2, sec(time to reach platform), n=6, p=0.02). The mice also showed reduced sensorimotor gating as assessed by PPI, all defects observed in the YAC128 HD mice.
In contrast to YAC mice, an earlier, more severe phenotype was observed in the HIP14-/- mice, with specific striatal volume loss at 1 month rather than at 8 months in the YAC128 mice. The degree of striatal loss at 1month in HIP14-/- mice was similar to that at 1 year in YAC128 mice. HIP14 palmitoylates htt and several other proteins involved in synaptic function. One possibility for the enhanced phenotype is altered palmitoylation of other neuronal proteins identified as substrates of HIP14. Indeed, palmitoylation of psd95, GluR1 and GluR2 are reduced in HIP14-/- brains.
Conclusion: Palmitoylation of proteins is essential for their trafficking to and turnover at specific plasma membrane sites. Thus, altered localization and turnover of glutamate receptors caused by aberrant palmitoylation may underlie the striatal loss in HIP14-/- mice. The similarity in phenotype between HIP14-/- and HD mice indicates that palmitoylation may play an essential role in the cell death pathways in HD.
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