Publication Date:
2013-05-31
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020154/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020154/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Park, Jeehye -- Al-Ramahi, Ismael -- Tan, Qiumin -- Mollema, Nissa -- Diaz-Garcia, Javier R -- Gallego-Flores, Tatiana -- Lu, Hsiang-Chih -- Lagalwar, Sarita -- Duvick, Lisa -- Kang, Hyojin -- Lee, Yoontae -- Jafar-Nejad, Paymaan -- Sayegh, Layal S -- Richman, Ronald -- Liu, Xiuyun -- Gao, Yan -- Shaw, Chad A -- Arthur, J Simon C -- Orr, Harry T -- Westbrook, Thomas F -- Botas, Juan -- Zoghbi, Huda Y -- HD024064/HD/NICHD NIH HHS/ -- MC_U127081014/Medical Research Council/United Kingdom -- NS42179/NS/NINDS NIH HHS/ -- P30 HD024064/HD/NICHD NIH HHS/ -- R01 NS027699/NS/NINDS NIH HHS/ -- R01 NS042179/NS/NINDS NIH HHS/ -- T32 GM007526/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jun 20;498(7454):325-31. doi: 10.1038/nature12204. Epub 2013 May 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23719381" target="_blank"〉PubMed〈/a〉
Keywords:
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
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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