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PARP-1 Inhibition Is Neuroprotective in the R6/2 Mouse Model of Huntington’s Disease

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  • Antonella Cardinale
  • Emanuela Paldino
  • Carmela Giampà
  • Giorgio Bernardi
  • Francesca R Fusco

Abstract

Poly (ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that is involved in physiological processes as DNA repair, genomic stability, and apoptosis. Moreover, published studies demonstrated that PARP-1 mediates necrotic cell death in response to excessive DNA damage under certain pathological conditions. In Huntington’s disease brains, PARP immunoreactivity was described in neurons and in glial cells, thereby suggesting the involvement of apoptosis in HD. In this study, we sought to determine if the PARP-1 inhibitor exerts a neuroprotective effect in R6/2 mutant mice, which recapitulates, in many aspects, human HD. Transgenic mice were treated with the PARP-1 inhibitor INO-1001 mg/Kg daily starting from 4 weeks of age. After transcardial perfusion, histological and immunohistochemical studies were performed. We found that INO 1001-treated R6/2 mice survived longer and displayed less severe signs of neurological dysfunction than the vehicle treated ones. Primary outcome measures such as striatal atrophy, morphology of striatal neurons, neuronal intranuclear inclusions and microglial reaction confirmed a neuroprotective effect of the compound. INO-1001 was effective in significantly increasing activated CREB and BDNF in the striatal spiny neurons, which might account for the beneficial effects observed in this model. Our findings show that PARP-1 inhibition could be considered as a valid therapeutic approach for HD.

Suggested Citation

  • Antonella Cardinale & Emanuela Paldino & Carmela Giampà & Giorgio Bernardi & Francesca R Fusco, 2015. "PARP-1 Inhibition Is Neuroprotective in the R6/2 Mouse Model of Huntington’s Disease," PLOS ONE, Public Library of Science, vol. 10(8), pages 1-22, August.
  • Handle: RePEc:plo:pone00:0134482
    DOI: 10.1371/journal.pone.0134482
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    1. Joan S. Steffan & Laszlo Bodai & Judit Pallos & Marnix Poelman & Alexander McCampbell & Barbara L. Apostol & Alexsey Kazantsev & Emily Schmidt & Ya-Zhen Zhu & Marilee Greenwald & Riki Kurokawa & David, 2001. "Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila," Nature, Nature, vol. 413(6857), pages 739-743, October.
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