Dysregulation of poly ADP ribose signaling in HD and its potential as a therapeutic target
Bibliographic record
Abstract
Abstract Huntington’s disease (HD) age of onset is correlated to CAG repeat length within the disease-causing gene but varies by decades between individuals. Genetic causes for this disease modification were linked to DNA repair, redox regulation, and mitochondrial health pathways by genome-wide association studies. The huntingtin protein responds to reactive oxygen species by moving to the nucleus where it localizes to sites of DNA damage and acts as a scaffold for DNA repair factors. We therefore sought to identify huntingtin-interacting proteins in the context of oxidative stress. We found a large degree of overlap with databases of proteins modified by poly ADP ribose (PAR), the moiety generated upon activation of poly ADP ribose polymerases (PARPs) by DNA damage. We show that purified huntingtin protein binds PAR in vitro and that huntingtin co-immunoprecipitates PARylated proteins upon oxidative stress. We and others have previously observed elevated levels of DNA damage in HD cells and tissues, which may reflect suboptimal huntingtin function as a DNA repair factor scaffold. Unrepaired DNA damage leads to prolonged activation of PARPs and overproduction of PAR. We therefore examined PAR levels in HD patient-derived fibroblasts and found them to be elevated compared to controls. Unrelenting PAR production causes ATP depletion, mitochondrial failure and energy crisis through multiple mechanisms, providing a link between GWAS genetic modifier pathways and long-observed energy deficits in HD. PAR also acts as a mediator of cell death through parthanatos. Current efforts are therefore focused on determining whether inhibition of PAR production can alleviate ATP/ADP ratio phenotypes and cell death in HD cells. We seek to determine if PARP enzymatic inhibition, or suppression of PARP expression is the target for HD. Recent reports of the role of PAR in Parkinson’s and other neurodegenerative diseases suggests a common pathogenic mechanism and that repurposing PARP inhibitors, some of which have been developed and FDA-approved as cancer drugs, may provide a viable therapeutic strategy.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".