PARP: targeting a cancer enzyme for disease modification in Parkinson’s

Original articles: 

  • Cancer enzyme affects Parkinson’s disease, Science: November 2, 2018. 
  • Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson’s disease, Science: November 2, 2018.

The takeaway

PARP, an enzyme involved in cancer, mediates the toxic effects of misfolded alpha-synuclein on neurons. PARP inhibition increases dopamine neuron survival.

Why is it important?

This work highlights PARP as an important target for disease modifying efforts in Parkinson’s.

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IMPACT

  • Novelty 80% 80%
  • Proximity 80% 80%
  • Deliverability 70% 70%

Impact Opinion

“Prof Ted and Valina Dawson have been investigating the role of PARP in Parkinson’s for more than a decade, and their latest research report represents a major step forward in our understanding of how this protein may be involved in the condition. A really appealing aspect of the study is that clinically available PARP inhibitors have such a powerful effect in multiple models of PD. The idea of repurposing them for Parkinson’s, however, may be complicated by toxicity/safety and brain penetrance issues, which may be solveable with re-formulation. But this report is extremely encouraging research.”

Background

Poly ADP ribose (PAR) polymerase, known as PARP1, is an enzyme involved in repairing DNA as cells routinely divide, and also involved in a programmed cell death, known as parthanatos (thanatos means death in Greek). Many years ago, researchers noticed that when neurons were stressed by damage or a neurotoxic chemical, they would start to produce high levels of levels of PARP1. When they blocked this increase in PARP1 levels, the researchers found that those neurons would survive better than neurons in which PARP1 levels were allowed to increase. Other researchers also noticed that dopamine neurons in the brains of people who passed away with Parkinson’s had elevated levels of PARP1. These findings resulted in the researchers asking if PARP1 could be involved with PD.

The details

Researchers at Johns Hopkins sought to understand how misfolded alpha-synuclein causes neuronal death. They treated cultured dopamine neurons with preformed toxic forms of alpha-synuclein and found that this led to an increase in cell death as well as raised levels of PARP and PAR. It is interesting that alpha synuclein can trigger this form of cell death. Moreover, the researchers found that PAR – which is normally present in cells but can be further triggered by misfolded alpha-synuclein  – interacts with normal alpha-synuclein in a toxic, forward feeding manner, causing more misfolding and further DNA damage. This DNA damage triggers further PARP1 activation and a vicious cycle ensues.

To further test the role of PARP1 in dopamine neuron death, the researchers deleted the PARP gene and also inhibited PARP using two different PARP inhibitor drugs, in neuron cultures as well as mice. The result was a significant increase in neuron survival and a drop in PARP1 and PAR.

The researchers also looked at the postmortem brains of people with Parkinson’s and they found higher levels of PAR (compared to healthy control samples) in the region where the dopamine neurons reside. These results lead the researchers to conclude that PARP1 inhibitors should be further investigated for use in Parkinson’s.

Next steps

PARP inhibitors are used as chemotherapy in different types of cancer. The Linked Clinical Trials programme, which focuses largely on repurposing existing drugs for different conditions as potential disease modifiers for Parkinson’s, has been focusing on several PARP inhibitors aimed at disease modification over the last 6 years (such as olaparib, rucaparib, and niraparib). The major rate limiting step have been concerns over safety and tolerability associated with the longer term administration that would be required for Parkinson’s. The current work indicates that relatively low levels of these drugs may be required to achieve clinical benefit, which is encouraging.

Further research, however, is needed into PAPR inhibitors, as well as their potential to be used in combination with other experimental disease modifying drugs such as exenatide, in efforts to reduce the toxic effects of misfolded alpha-synuclein on neurons as well as glia.

Original articles: 

  • Cancer enzyme affects Parkinson’s disease, Science: November 2, 2018. 
  • Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson’s disease, Science: November 2, 2018.
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