한빛사 논문
Saurav Brahmachari,1,2,3,* Saebom Lee,1,2,* Sangjune Kim,1,2,* Changqing Yuan,1,2,3 Senthilkumar S. Karuppagounder,1,2,3 Preston Ge,1,2,3 Rosa Shi,1,2,3 Esther J. Kim,1,2,3 Alex Liu,1,2,3 Donghoon Kim,1,2,5 Stephan Quintin,1,2 Haisong Jiang,1,2,3 Manoj Kumar,1,2,3 Seung Pil Yun,1,2,3 Tae-In Kam,1,2,3 Xiaobo Mao,1,2,3 Yunjong Lee,1,2,3 Deborah A. Swing,6 Lino Tessarollo,6 Han Seok Ko,1,2,5,‡ Valina L. Dawson1,2,3,4,7,‡ and Ted M. Dawson1,2,3,7,8,‡
1 Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
3 Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130–2685, USA
4 Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
5 Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130–2685, USA
6 Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick,Maryland, USA
7 Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
8 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
*,‡These authors contributed equally to this work.
Correspondence to: Ted M. Dawson
Neuroregeneration and Stem Cell Programs Institute for Cell Engineering Johns Hopkins University School of Medicine 733 North Broadway, Suite 731
Abstract
α-Synuclein misfolding and aggregation plays a major role in the pathogenesis of Parkinson’s disease. Although loss of function mutations in the ubiquitin ligase, parkin, cause autosomal recessive Parkinson’s disease, there is evidence that parkin is inactivated in sporadic Parkinson’s disease. Whether parkin inactivation is a driver of neurodegeneration in sporadic Parkinson’s disease or a mere spectator is unknown. Here we show that parkin in inactivated through c-Abelson kinase phosphorylation of parkin in three α-synuclein-induced models of neurodegeneration. This results in the accumulation of parkin interacting substrate protein (zinc finger protein 746) and aminoacyl tRNA synthetase complex interacting multifunctional protein 2 with increased parkin interacting substrate protein levels playing a critical role in α-synuclein-induced neurodegeneration, since knockout of parkin interacting substrate protein attenuates the degenerative process. Thus, accumulation of parkin interacting substrate protein links parkin inactivation and α-synuclein in a common pathogenic neurodegenerative pathway relevant to both sporadic and familial forms Parkinson’s disease. Thus, suppression of parkin interacting substrate protein could be a potential therapeutic strategy to halt the progression of Parkinson’s disease and related α-synucleinopathies.
Keywords: zinc finger protein 746, PARIS, α-synuclein, parkin, Parkinson’s disease
논문정보
관련 링크
연구자 키워드
연구자 ID
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기