Researchers at the Johns Hopkins School of Medicine have published a research report in Science that points not only towards a specific pathway of neurodegeneration for Parkinson's, but also and importantly, highlights a therapeutic target for which clinically-approved drugs are already available!

In the brain, Parkinson's is characterised by two main features: 1. the loss of specific populations of cells (such as the dopamine producing neurons), and 2. by the accumulation of a protein called alpha synuclein in aggregated clusters. A team of scientists at Johns Hopkins led by Professor Ted Dawson (a member of CPT's International Linked Clinical Trials committee) and Professor Valina - have found that high levels of the aggregated forms of the alpha synuclein can kill neurons via a particular cell death pathway called 'parthanatos'. 

Parthanatos results from the over production of a protein called PAR, which is generated by an enzyme called PARP1. The researchers observed that the aggregated form of alpha synuclein stimulates the activity of PARP1, which results in an increase in levels of PAR and leads to cell death. The scientists also reported that high levels of PAR resulted in an acceleration of alpha synuclein protein aggregation - the presence of PAR was causing alpha synuclein to aggregate. They proposed that this situation could create a feed-forward loop in which PAR aggregates alpha synuclein which then activates PARP1 leading to further increased levels of PAR. And to support this idea, the researchers found increased levels of PAR in the brains of people with Parkinson's.

Of particular interest, however, is that the team of investigators found that they could block the parthanatos cell death by treating the affected cells with medicine already available in the form of 'PARP1 inhibitors'. These drugs are currently being used in the treatment of certain types of cancer. In models of Parkinson's, treatment with the PARP1 inhibitors not only reduced levels of alpha synuclein, but also prevented the loss of dopamine neurons.

Thus, strategies aimed at inhibiting the activation of PARP-1 could hold promise for disease-modifying therapy in Parkinson's and related conditions involving alpha synuclein aggregation. Moreover, assessment of PAR levels in people with Parkinson's could serve as a biomarker for disease-modifying therapies.

The possibility of repurposing this class of drugs for Parkinson's is currently being assessed. 

CPT's Dr Richard Wyse and International Linked Clinical Trials Chair Prof. Patrik Brundin have provided a commentary on this paper - http://science.sciencemag.org/content/362/6414/521

To read a more in depth discussion of the role of PARP-1 in Parkinson's read The Science of Parkinson's - PARP.