Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss

Yunjong Lee, Senthilkumar Karuppagounder, Joo Ho Shin, Yun Il Lee, Hanseok Seok Ko, Debbie Swing, Haisong Jiang, SungUng Kang, Byoung Dae Lee, Ho Chul Kang, Donghoon Kim, Lino Tessarollo, Valina 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

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Amino Acyl-tRNA Synthetases
Dopaminergic Neurons
Parkinson Disease
Proteins
Ubiquitin-Protein Ligases
Gene Deletion
Transgenic Mice
DNA Damage
Disease Progression
Mutation
Poly (ADP-Ribose) Polymerase-1
Brain
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Neuroscience(all)

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Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss. / Lee, Yunjong; Karuppagounder, Senthilkumar; Shin, Joo Ho; Lee, Yun Il; Ko, Hanseok Seok; Swing, Debbie; Jiang, Haisong; Kang, SungUng; Lee, Byoung Dae; Kang, Ho Chul; Kim, Donghoon; Tessarollo, Lino; Dawson, Valina; Dawson, Ted M.

In: Nature Neuroscience, Vol. 16, No. 10, 10.2013, p. 1392-1400.

Research output: Contribution to journalArticle

Lee, Y, Karuppagounder, S, Shin, JH, Lee, YI, Ko, HS, Swing, D, Jiang, H, Kang, S, Lee, BD, Kang, HC, Kim, D, Tessarollo, L, Dawson, V & Dawson, TM 2013, 'Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss', Nature Neuroscience, vol. 16, no. 10, pp. 1392-1400. https://doi.org/10.1038/nn.3500
Lee, Yunjong ; Karuppagounder, Senthilkumar ; Shin, Joo Ho ; Lee, Yun Il ; Ko, Hanseok Seok ; Swing, Debbie ; Jiang, Haisong ; Kang, SungUng ; Lee, Byoung Dae ; Kang, Ho Chul ; Kim, Donghoon ; Tessarollo, Lino ; Dawson, Valina ; Dawson, Ted M. / Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss. In: Nature Neuroscience. 2013 ; Vol. 16, No. 10. pp. 1392-1400.
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