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

Authors
Lee, Y; Karuppagounder, SS; Shin, JH; Lee, YI; Ko, HS; Swing, D; Jiang, H; Kang, SU; Lee, BD; Kang, HC; Kim, D; Tessarollo, L; Dawson, VL; Dawson, TM
Citation
Nature neuroscience, 16(10):1392-1400, 2013
Journal Title
Nature neuroscience
ISSN
1097-62561546-1726
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.
MeSH terms
Age FactorsAnimalsCarrier Proteins/genetics/*metabolismCell Aging/*geneticsCell Death/geneticsDopaminergic Neurons/*pathology/*physiologyFemaleGene DeletionHumansMiceMice, Inbred C57BLMice, TransgenicPC12 CellsPoly(ADP-ribose) Polymerases/*antagonists & inhibitors/geneticsPregnancyRats
DOI
10.1038/nn.3500
PMID
23974709
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
AJOU Authors
강, 호철
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