RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1.

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.

• Authors: Jeehye Park, Ismael Al-Ramahi, Qiumin Tan, Nissa Mollema, Javier R Diaz-Garcia, Tatiana Gallego-Flores, Hsiang-Chih Lu, Sarita Lagalwar, Lisa Duvick, Hyojin Kang, Yoontae Lee, Paymaan Jafar-Nejad, Layal S Sayegh, Ronald Richman, Xiuyun Liu, Yan Gao, Chad A Shaw, J Simon C Arthur, Harry T Orr, Thomas F Westbrook, Juan Botas, Huda Y Zoghbi
• Journal: Nature (Nature) Vol. 498 Issue 7454 Pg. 325-331 (Jun 20 2013) ISSN: 1476-4687 [Electronic] England
• PMID: 23719381 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ATXN1 protein, human
• Ataxin-1
• Ataxins
• Atxn1 protein, mouse
• Nerve Tissue Proteins
• Nuclear Proteins
• Ribosomal Protein S6 Kinases, 90-kDa
• mitogen and stress-activated protein kinase 1
• Mitogen-Activated Protein Kinases
• ras Proteins

Topics

• Amino Acid Sequence
• Animals
• Animals, Genetically Modified
• Ataxin-1
• Ataxins
• Cell Line, Tumor
• Disease Models, Animal
• Down-Regulation (drug effects)
• Drosophila melanogaster (genetics, metabolism)
• Female
• Humans
• MAP Kinase Signaling System (drug effects)
• Male
• Mice
• Mitogen-Activated Protein Kinases (metabolism)
• Molecular Sequence Data
• Molecular Targeted Therapy
• Nerve Tissue Proteins (chemistry, genetics, metabolism, toxicity)
• Nuclear Proteins (chemistry, genetics, metabolism, toxicity)
• Phosphorylation
• Protein Stability (drug effects)
• Ribosomal Protein S6 Kinases, 90-kDa (deficiency, genetics, metabolism)
• Spinocerebellar Ataxias (metabolism, pathology)
• Transgenes
• ras Proteins (metabolism)