Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss

Yunjong Lee, Senthilkumar S. Karuppagounder, Joo Ho Shin, Yun Il Lee, Han Seok Ko, Debbie Swing, Haisong Jiang, Sung Ung Kang, Byoung Dae Lee, Ho Chul Kang, Donghoon Kim, Lino Tessarollo, Valina L. Dawson, Ted M. Dawson

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1392-1400
Number of pages9
JournalNature neuroscience
Volume16
Issue number10
DOIs
StatePublished - Oct 2013

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss'. Together they form a unique fingerprint.

  • Cite this