한빛사논문
- 조회4,791
Abstract
Jeehye Park1,2,3*, Ismael Al-Ramahi1,2*, Qiumin Tan1,2,3, Nissa Mollema4,5, Javier R. Diaz-Garcia1,2, Tatiana Gallego-Flores1,2, Hsiang-Chih Lu2,6, Sarita Lagalwar4,5, Lisa Duvick4,5, Hyojin Kang1,2†, Yoontae Lee1,2,3†, Paymaan Jafar-Nejad1,2, Layal S. Sayegh1,2, Ronald Richman1,2,3, Xiuyun Liu1,2,3, Yan Gao1,2, Chad A. Shaw1, J. Simon C. Arthur7, Harry T. Orr4,5, Thomas F. Westbrook1,6,8, Juan Botas1,2 & Huda Y. Zoghbi1,2,3,6
1Department of Molecular andHumanGenetics, Baylor College of Medicine, Houston, Texas 77030, USA. 2Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, Texas 77030, USA. 3Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA. 4Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA. 5Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA. 6Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA. 7MRCProtein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK. 8Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. †Present addresses: Supercomputing Center, Korea Institute of Science and Technology Information, Daejeon 305-806, South Korea (H.K.); Department of Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, South Korea (Y.L.).
*These authors contributed equally to this work.
Correspondence to: Harry T. Orr or Thomas F. Westbrook or Juan Botas or Huda Y. Zoghbi
Abstract
Many neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and polyglutamine diseases, share a common pathogenic mechanism: the abnormal accumulation of disease-causing proteins, due to either the mutant protein’s resistance to degradation or overexpression of the wild-type protein. We have developed a strategy to identify therapeutic entry points for such neurodegenerative disorders by screening for genetic networks that influence the levels of disease-driving proteins. We applied this approach, which integrates parallel cell-based and Drosophila genetic screens, to spinocerebellar ataxia type 1 (SCA1), a disease caused by expansion of a polyglutamine tract in ataxin 1 (ATXN1). Our approach revealed that downregulation of several components of the RAS?MAPK?MSK1 pathway decreases ATXN1 levels and suppresses neurodegeneration in Drosophila and mice. Importantly, pharmacological inhibitors of components of this pathway also decrease ATXN1 levels, suggesting that these components represent new therapeutic targets in mitigating SCA1. Collectively, these data reveal new therapeutic entry points for SCA1 and provide a proof-of-principle for tackling other classes of intractable neurodegenerative diseases.
논문정보
- Research article
- 2013년 05월 (BRIC 등록일 2013-06-03)
- 국외 연구진
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