Blog post by Dr. Tamara Maiuri
Most researchers would agree, it feels like we just can’t get enough experiments done, and those, not fast enough. But it’s useful to pause the benchwork from time to time and review a project–what worked, what didn’t, and what we may have missed in our rush to move on to the next thing.
That’s what I’ve done at the end of Year 2 of the HDSA Berman-Topper Fellowship. One of the requirements of the fellowship is that you summarize your work in a report at the end of each year–a daunting task, but well worth the time. It certainly put things in perspective. In a nutshell, what the report says is:
The major finding of the first year of the Berman-Topper fellowship was that many proteins that interact with the huntingtin protein bear a molecule involved in the DNA repair process: poly ADP ribose (PAR). This led us to investigate a connection between huntingtin and PAR signaling in the second year of the fellowship. Methods for detecting PAR were optimized, and a hyper-PAR phenotype was identified in HD patient fibroblasts and in HD mouse striatal precursor cells. The huntingtin-PAR interaction was confirmed in cells and in vitro.
Elevated PAR levels may arise from unrepaired DNA damage and lead to cellular energy deficits, both of which have been observed in many HD models and tissues. Our results introduce the exciting possibility that inhibitors of poly ADP ribose polymerase (PARP), drugs that have already been through clinical trials for a number of cancers, can be explored as a therapeutic option for HD. This is an avenue that has not been considered in the past, and shows promise for other neurodegenerative diseases including Parkinson’s, Alzheimer’s, and ALS.
What is needed at this point is rigorous pre-clinical testing of
- Whether PARP inhibitors affect HD model phenotypes
- Safety profiles of PARP inhibitor drugs that would make promising therapeutic leads
Preliminary experiments suggest that PARP inhibitors, which trap PARP at DNA, are co-trapping huntingtin at DNA. This is not likely to be beneficial as it may interfere with huntingtin function. As such, PARP lowering strategies will also be considered in the final year of the fellowship. Complete characterization of the mechanism and function of huntingtin PAR binding is also underway.
The full report, with links to all the raw data, is available on Zenodo. I have also deposited last year’s year-end report and the shorter quarterly reports for 2017-2018.
In reviewing the year’s data, I realized that I failed to deposit a few experiments to Zenodo. I’m doing so now, and I’ll post about them in the coming weeks.