title: Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss.
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.
authors: 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.
authors: Yunjong
authors: Y
authors: Lee
authors: Senthilkumar S
authors: SS
authors: Karuppagounder
authors: Joo-Ho
authors: JH
authors: Shin
authors: Yun-Il
authors: YI
authors: Lee
authors: Han Seok
authors: HS
authors: Ko
authors: Debbie
authors: D
authors: Swing
authors: Haisong
authors: H
authors: Jiang
authors: Sung-Ung
authors: SU
authors: Kang
authors: Byoung Dae
authors: BD
authors: Lee
authors: Ho Chul
authors: HC
authors: Kang
authors: Donghoon
authors: D
authors: Kim
authors: Lino
authors: L
authors: Tessarollo
authors: Valina L
authors: VL
authors: Dawson
authors: Ted M
authors: TM
authors: Dawson
mesh_terms: D000367:Age Factors; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D059290:Dopaminergic Neurons / Q000473:pathology* / Q000502:physiology*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins; D016716:PC12 Cells; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D011247:Pregnancy; D051381:Rats
chemical_list: C575685:AIMP2 protein, human; D002352:Carrier Proteins; D009687:Nuclear Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
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