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한빛사논문, 상위피인용논문

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Johns Hopkins University School of Medicine

Nat. Neurosci., 16, 1392–1400, Published online 25 August 2013 | doi:10.1038/nn.3500 Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss

Yunjong Lee^1-4, Senthilkumar S Karuppagounder^1,3,4, Joo-Ho Shin^1,3-5, Yun-Il Lee^1,3,12, Han Seok Ko^1,3,6, Debbie Swing⁷, Haisong Jiang^1,3,4, Sung-Ung Kang^1,3,4, Byoung Dae Lee^1,3,8, Ho Chul Kang^1,3,9,10, Donghoon Kim^1,3,6, Lino Tessarollo⁷, Valina L Dawson^1-4,11,13 & Ted M Dawson^1,3,4,11,13

¹Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ²Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ³Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ⁴Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana, USA. ⁵Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea. ⁶Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana, USA. ⁷Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA. ⁸Age-Related and Brain Disease Research Center, Department of Neuroscience, Kyung Hee University, Seoul, South Korea. ⁹Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea. ¹⁰Department of Physiology, Ajou University School of Medicine, Suwon, Korea. ¹¹Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ¹²Present address: Well-Aging Research Center, Samsung Advanced Institute of Technology, Yongin-si, Korea. ¹³These authors contributed equally to this work.

Correspondence to: Valina L Dawson or Ted M Dawson

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.

논문정보

형식Research article
게재일2013년 08월 (BRIC 등록일 2013-10-04)
연구진국내+국외 연구진
분야 의약학 > 신경의학
피인용횟수120회 이상 인용된 논문 (상위피인용논문 등록일 2021-09-29)

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