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Nat Neurosci. 2013 Oct;16(10):1392-400. doi: 10.1038/nn.3500. Epub 2013 Aug 25.

Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss.

Author information

1
1] Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [3] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [4] Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana, USA.

Abstract

The defining pathogenic feature of Parkinson's disease is the age-dependent loss of dopaminergic neurons. Mutations and inactivation of parkin, an ubiquitin E3 ligase, induce Parkinson's disease through accumulation of pathogenic substrates. We found that transgenic overexpression of a parkin substrate, aminoacyl-tRNA synthetase complex interacting multifunctional protein-2 (AIMP2), led to a selective, age-dependent, progressive loss of dopaminergic neurons via activation of poly(ADP-ribose) polymerase-1 (PARP1). AIMP2 accumulation in vitro and in vivo resulted in PARP1 overactivation and dopaminergic cell toxicity via direct association of these proteins in the nucleus, providing a path to PARP1 activation other than DNA damage. Inhibition of PARP1 through gene deletion or drug inhibition reversed behavioral deficits and protected against dopamine neuron death in AIMP2 transgenic mice. These data indicate that brain-permeable PARP inhibitors could effectively delay or prevent disease progression in Parkinson's disease.

PMID:
23974709
PMCID:
PMC3785563
DOI:
10.1038/nn.3500
[Indexed for MEDLINE]
Free PMC Article

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