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Evaluation of a Low-Toxicity PARP Inhibitor as a Neuroprotective Agent for Parkinson’s Disease

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Abstract

Repurposing PARP-1 inhibitors (PARPi) for non-oncological applications offers an attractive therapeutic strategy for pathological conditions characterized by PARP-1 hyperactivity. In the context of Parkinson’s disease (PD), PARP-1 hyperactivity has been linked to neuronal death and disease progression. From a therapy perspective, the evaluation of PARPi as neuroprotective agents may offer a new therapeutic alternative for neurodegenerative disorders. An ideal PARPi needs to inhibit PARP-1 hyperactivity while also limiting downstream DNA damage and cellular toxicity—an effect that is attractive in cancer but far from ideal in neurological disease applications. Consequently, in this study, we set out to evaluate the neuroprotective properties of a previously reported low-toxicity PARPi (10e) using in vitro neuronal models of PD. 10e is a structural analogue of FDA-approved PARPi olaparib, with high PARP-1 affinity and selectivity. Our studies revealed that 10e protects neuronal cells from oxidative stress and DNA damage. In addition, 10e exhibits neuroprotective properties against α-synuclein pre-formed fibrils (αSyn PFF) mediated effects, including reduction in the levels of phosphorylated αSyn and protection against abnormal changes in NAD+ levels. Our in vitro studies with 10e provide support for repurposing high-affinity and low-toxicity PARPi for neurological applications and lay the groundwork for long-term therapeutic studies in animal models of PD.

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Data and Materials Availability

All data generated and analyzed in this study are included in this published article.

Abbreviations

PARP-1:

Poly(ADP-ribose) polymerase-1

PARPi:

PARP inhibitor

PD:

Parkinson’s disease

αSyn:

Alpha-synuclein

PFF:

Pre-formed fibrils

PAR:

Poly (ADP-ribose)

NAD+ :

Nicotinamide adenine dinucleotide

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Acknowledgements

SH-SY5Y-WT and SH-SY5Y-αSyn cells were a gift from Dr. Harry Ischiropoulos, University of Pennsylvania. IMR-5 cells were a gift from Dr. John Maris, University of Pennsylvania. The plasmid encoding the human αSyn sequence was a gift from Dr. James Petersson, University of Pennsylvania.

Funding

This research was supported by the Michael J. Fox Foundation (R.H.M.) and U19-NS110456 (R.H.M.) and supported in part by T32GM008076 (L.N.P.).

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Authors and Affiliations

  1. Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Laura N. Puentes

  2. Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Zsofia Lengyel-Zhand, Sean W. Reilly & Robert H. Mach

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  1. Laura N. Puentes
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  2. Zsofia Lengyel-Zhand
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  3. Sean W. Reilly
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Contributions

L.N.P. designed the experiments presented in this study and performed all the cell/biochemical and microscopy-based experiments. Z.L.Z. helped produce all the purified proteins and fibrils used in this project. L.N.P. and Z.L.Z. prepared the manuscript. S.W.R. synthesized 10e and the other olaparib analogues described in this manuscript. Z.L.Z. and R.H.M provided support with experimental design.

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Correspondence to Robert H. Mach.

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Puentes, L.N., Lengyel-Zhand, Z., Reilly, S.W. et al. Evaluation of a Low-Toxicity PARP Inhibitor as a Neuroprotective Agent for Parkinson’s Disease. Mol Neurobiol 58, 3641–3652 (2021). https://doi.org/10.1007/s12035-021-02371-4

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  • DOI: https://doi.org/10.1007/s12035-021-02371-4

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