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.
Highlights
Huntington’s disease (HD) is a severe neurodegenerative disorder, genetically transmitted in an autosomal dominant fashion, and it is characterized by motor dysfunction, cognitive decline and psychiatric disorder [1,2]
The present data show that Poly (ADP-ribose) polymerase (PARP) inhibition by INO-1001 exerts a beneficial effect on the R6/2 mouse model of HD in terms of survival, neurological impairment and neuroprotection
These effects in promoting neurological recovery demonstrate that the PARP inhibitor used in this study is effective in suppressing PARP activation caused by HD degeneration
Summary
Huntington’s disease (HD) is a severe neurodegenerative disorder, genetically transmitted in an autosomal dominant fashion, and it is characterized by motor dysfunction, cognitive decline and psychiatric disorder [1,2]. The IT15 gene [3] encoding for huntingtin protein consists in a CAG expansion beyond the normal 10–35 repeat range [4]. HD pathology is characterized by the formation of neuronal intranuclear inclusions that are constituted by mutated huntingtin [5]. Such inclusions interact with and impair several cellular functions [6]. Apoptosis gives rise to the removal of damaged or unnecessary cells, and this phenomenon occurs physiologically during development or after DNA damage and normal tissue homeostasis [7, 8, 9]. The activation of PLOS ONE | DOI:10.1371/journal.pone.0134482 August 7, 2015
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