Dysregulation of poly ADP ribose signaling in HD and its potential as a therapeutic target
| Main Authors: | Maiuri, Tamara, Barba, Carlos, Harding, Rachel, Truant, Ray |
|---|---|
| Format: | Proceeding poster |
| Bahasa: | eng |
| Terbitan: |
, 2019
|
| Subjects: | |
| Online Access: |
https://zenodo.org/record/2617679 |
Daftar Isi:
- 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.
- This work is funded by the HDSA Berman/Topper HD Career Development Fellowship. This poster was presented at the 2019 HD Therapeutics conference in Palm Springs, CA, Feb 25-28.