Blog post by Dr. Tamara Maiuri
I would like to start this post by saying that the ideas below are PURELY SPECULATIVE at this point. But I’m excited about them and feel they definitely warrant further investigation.
So here’s the deal: In a study funded by the HDSA Berman/Topper fellowship, we have found that the huntingtin protein interacts with proteins modified by poly ADP ribose (PAR), and that PAR levels are elevated in cells from HD patients.
What is PAR?
PAR is a branched chain-like molecule that acts as a recruitment scaffold for DNA repair proteins. It’s made by an enzyme called poly ADP ribose polymerase (PARP) upon DNA damage (we and others also see elevated levels of DNA damage in HD patient cells [1–3]).
What is PARP?
There are several PARP enzymes, but let’s concentrate on PARP1 for now. PARP1 is a major player in the DNA damage response.
PARP1 uses a building material called NAD+ to generate the branched PAR chains that recruit DNA repair factors. The problem is, NAD+ is needed for other things in the cell, especially for converting food into energy. So PARP1 activity is great for a quick response to clear up some DNA damage, but if the damage is too great (or if it’s prolonged), then energy levels in the cell get depleted.
There are several negative consequences if PARP activity goes on too long. Let’s compare a list of these negative consequences to what is seen in HD models and patients (NB: these phenotypes are very much interrelated):
PARP hyper-activation phenotypes
|ATP depletion [4–7]||ATP depletion [8–13]|
|Mitochondrial dysfunction [14–17]||Mitochondrial dysfunction (reviewed in )|
|Energy crisis [19,20]||Energy crisis (reviewed in )|
|Cell death (through parthanatos) [22,23]||Cell death through apoptosis, necrosis (parthanatos not yet tested) (reviewed in )|
|Neuroinflammation [25–29]||Neuroinflammation [30–32]|
|Transcriptional and chromatin changes (reviewed in )||Transcriptional and chromatin changes (reviewed in [34,35])|
|Autophagy and protein clearance (reviewed in [36,37])||Autophagy and protein clearance (reviewed in [38,39])|
Just looking at this list, even if we had no indication that PAR is dysregulated in HD, I would say it’s worth looking into! Turns out, PARP hyper-activation has been linked to other neurodegenerative diseases (reviewed in ), most recently Parkinson’s .
The good news
The cancer field has done decades of work to understand how to inhibit PARPs. I didn’t think this would be much use to us in the HD field, since the point of cancer drugs is to KILL TUMOUR CELLS, while we are looking for drugs to KEEP NEURONS ALIVE.
I was disabused of this notion when I read a very nice review article called Opportunities for the repurposing of PARP inhibitors for the therapy of non-oncological diseases . The article recommends that for chronic, non-oncological indications where there is a significant unmet need, we should consider taking PARP inhibitors to trial.
Criteria for deciding whether to try PARP inhibitors for a non-oncological indication
Q: Is there preclinical data demonstrating the efficacy of PARP inhibition in clinically relevant preclinical models?
A: Not yet, but:
- PARP inhibition is beneficial in R6/2 mice [43,44]
- Truant lab student Carlos Barba is currently testing PARP inhibition in TruHD cells (and STHdh cells, although not as clinically relevant)
- We have also asked Chris Ross’s lab to test PARP inhibition in neurons expressing the huntingtin 1-586 fragment (this is an overexpression system, but at least it is in neurons)
Q: Is there human data confirming activation of PARP in the target organ?
A: Not yet, but:
- PAR levels are elevated in TruHD cells (results on Zenodo)
- Ted Dawson’s lab is looking at PAR levels in CSF from HD patients (collected through HDClarity). They previously found elevated levels of PAR in CSF from Parkinson’s patients 
- Simonetta Sipione’s lab is looking at PAR levels in HD mouse brains (this is not human data though)
- I’m currently looking at PARP activity in blood cells from HD patients
Q: Would the duration of treatment be short, to limit potential side effects?
A: Unfortunately, no. But intermittent administration (“drug holidays”) could be an option.
Q: Are existing therapeutic alternatives insufficient?
Q: Is HD severe enough to justify an attempt for novel therapies, especially in light of the potential “genotoxic baggage” that comes with PARP inhibition?
A: Hell yes.
Q: Would a trial be logistically feasible?
A: The HD community has proven that they are very capable of designing, recruiting, and running clinical trials.
Preclinical studies should:
- Use the drug that will eventually be trialed
- Use the most clinically relevant models
- Document the drug effects on DNA and chromosomal integrity (for ideas about safety)
The Truant lab works with preclinical systems. We are doing our best to make sure these preclinical studies are done properly so they can be most informative going forward. All of my results will be shared openly through this blog and our Zenodo Community. I welcome any comments or suggestions about how we might test PARP and PAR in HD systems. And now, back to the bench!
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