Regulation of huntingtin palmitoylation and its role in Huntington Diseases
Bibliographic record
Abstract
Huntington’s Disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor, cognitive, and psychiatric deficits and selective neuronal cell death. The causative mutation in HD is an expansion of the N-terminal polyglutamine tract in huntingtin (htt), which results in altered trafficking of mutant htt and enhanced toxicity to striatal neurons. Post-translational modification by the lipid palmitate has been shown to play a critical role in the trafficking and function of many proteins, including htt. It has been previously demonstrated that huntingtin-interacting protein 14 (HIP14) is a palmitoyl transferase that palmitoylates htt. Previous characterization of HIP14 demonstrated a reduced interaction with mutant htt resulting in reduced palmitoylation, suggesting that palmitoylation may play a role in the pathogenesis of HD. Most recently, we have identified cysteine 214 as a major site of htt palmitoylation in the N-terminus of htt, close to the site of polyglutamine expansion. It was demonstrated that mutation of this site, rendering htt palmitoylation-resistant, results in increased neuronal toxicity, enhanced inclusion formation, and in altered trafficking of htt. Remarkably, mutation of the palmitoylation site in wild type htt also resulted in enhanced toxicity similar to that seen in mutant htt. Together, these previous studies suggest a critical role of palmitoylation in htt trafficking and function. Based on this preliminary work, we are characterizing the enzymatic regulation of huntingtin palmitoylation. Exploring htt palmitoylation in a number of existing and new mouse models imparts key insights into how this process is regulated in vivo. We are also exploring the relationship between palmitoylation and other post-translational modifications of htt. These studies will lead to an understanding of the regulation of palmitoylation of huntingtin in vivo, as well as setting the precedent to understand the general role of palmitoylation in a wide range of other human diseases. Ultimately, this may lead to identification of new therapeutic targets and treatments for patients. F.B.J.Y. is supported by a Canadian Institutes of Health Research Walter and Jessie Boyd & Charles Scriver - Child and Family Research Institute - UBC MD/PhD Studentship Award. She also receives funding from the Michael Smith Foundation for Health Research as a Junior Trainee.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".