Hypothesis: Poly ADP ribose signaling is dysregulated in Huntington’s disease

Blog post by Dr. Tamara Maiuri

In a previous post, I described two new hypotheses generated by the findings of the HDSA-funded project looking for DNA repair-relevant huntingtin interacting proteins: that huntingtin binds poly ADP ribose (PAR), and that PAR signaling is dysregulated in HD. Last time, I reported our preliminary results supporting the first hypothesis. In the current post, I’ll report our first solid clue that PAR signaling may be dysregulated in HD: cells from HD patients have higher levels of PAR.

Let’s take a step back and look at the bigger picture for a moment. We know that suboptimal DNA repair plays a role in many neurodegenerative diseases [1–3], and DNA repair genes are implicated in HD symptom onset [4–6]. PAR synthesis is one of the first steps of DNA repair: PARP proteins recognize breaks in DNA and string together chains of PAR to help recruit the DNA repair machinery. If all goes well, the damage is repaired, the PAR is broken down for recycling, and the cell can go about its business as usual.

If the DNA is not repaired properly, then PARPs keep trying to bring in the recruits–they keep generating PAR. This wouldn’t be a huge problem, except that it seriously messes with the cell’s energy factories, aka mitochondria, in a number of ways. First off, the raw material that PARPs use to make PAR (called NAD+) is also needed by mitochondria to convert food into energy. If PARPs use up all the NAD+ stores, then cells undergo “energetic collapse” and die [7]. Bad news for high-energy-burning neurons. To make matters worse, the PAR produced in the nucleus also travels out to mitochondria and signals them to carry out a form of programmed cell death called Parthanatos [8]. Additional “nucleus-to-mitochondria death signaling” is thought to contribute to neuronal death in a number of neurodegenerative diseases [9,10]. In fact, many of the phenotypes we see in HD models and tissues could be explained by energy-draining hyper-PARylation, including protein aggregation [11–13], ATP depletion [14], and mitochondrial dysfunction [15].

We know that the expanded huntingtin protein is the cause of HD. We also know that huntingtin physically locates to sites of DNA damage and scaffolds DNA repair proteins [16], and that neurons are exposed to more and more DNA-damaging reactive oxygen species (ROS) as we age [17]. So, it makes sense to hypothesize that

Suboptimal mutant huntingtin function in the repair of nuclear DNA leads to hyper-PARylation in the high-ROS-load neurons of the striatum.

Suboptimal DNA repair by expanded huntingtin would have some observable consequences. For one, there would be more damaged DNA accumulating in HD tissues. This is been seen in patient cells by us [16] and others [18]. Secondly, we would expect hyper-PARylation if PARPs are constantly recognizing DNA breaks and generating PAR. That’s what Truant lab member Carlos Barba Bazan tested in these experiments deposited to Zenodo. Carlos found that PAR levels are elevated in two different HD patient cell lines compared to control.

We’re pretty excited about this finding and what it might mean. Is hyper-PARylation the culprit behind neuronal death in HD brains? We have more experiments to do before we know the answer to that. But one important clue is that a PARP inhibitor was beneficial in an HD mouse model [19,20]. PARP inhibitors are commonly used drugs in the cancer field, which means there’s a tonne of information about them, and many have already been tested for safety. We have a ways to go before we know whether any of these drugs might be suitable to treat HD. We will share all of our results about how important PAR signaling might be to HD as soon as we get them!

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