Publication Date:
2013-10-26
Description:
alpha-Synuclein (alpha-syn) is a small lipid-binding protein implicated in several neurodegenerative diseases, including Parkinson's disease, whose pathobiology is conserved from yeast to man. There are no therapies targeting these underlying cellular pathologies, or indeed those of any major neurodegenerative disease. Using unbiased phenotypic screens as an alternative to target-based approaches, we discovered an N-aryl benzimidazole (NAB) that strongly and selectively protected diverse cell types from alpha-syn toxicity. Three chemical genetic screens in wild-type yeast cells established that NAB promoted endosomal transport events dependent on the E3 ubiquitin ligase Rsp5/Nedd4. These same steps were perturbed by alpha-syn itself. Thus, NAB identifies a druggable node in the biology of alpha-syn that can correct multiple aspects of its underlying pathology, including dysfunctional endosomal and endoplasmic reticulum-to-Golgi vesicle trafficking.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3993916/" 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/PMC3993916/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tardiff, Daniel F -- Jui, Nathan T -- Khurana, Vikram -- Tambe, Mitali A -- Thompson, Michelle L -- Chung, Chee Yeun -- Kamadurai, Hari B -- Kim, Hyoung Tae -- Lancaster, Alex K -- Caldwell, Kim A -- Caldwell, Guy A -- Rochet, Jean-Christophe -- Buchwald, Stephen L -- Lindquist, Susan -- 5R01GM069530/GM/NIGMS NIH HHS/ -- F32GM099817/GM/NIGMS NIH HHS/ -- F32NS061419/NS/NINDS NIH HHS/ -- GM58160/GM/NIGMS NIH HHS/ -- K01 AG038546/AG/NIA NIH HHS/ -- R01 GM058160/GM/NIGMS NIH HHS/ -- R15 NS075684/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Nov 22;342(6161):979-83. doi: 10.1126/science.1245321. Epub 2013 Oct 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research (WIBR), Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24158909" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Benzimidazoles/chemistry/*pharmacology
;
Caenorhabditis elegans
;
Cells, Cultured
;
*Cytoprotection
;
Drug Evaluation, Preclinical
;
Endosomal Sorting Complexes Required for Transport/*genetics
;
Gene Regulatory Networks/*drug effects
;
Neurodegenerative Diseases/*metabolism
;
Neurons/*drug effects/metabolism
;
Neuroprotective Agents/*pharmacology
;
Parkinson Disease/metabolism
;
Rats
;
Saccharomyces cerevisiae/drug effects
;
Saccharomyces cerevisiae Proteins/*genetics
;
Small Molecule Libraries/chemistry/pharmacology
;
Ubiquitin-Protein Ligase Complexes/*genetics
;
Ubiquitin-Protein Ligases/*genetics
;
alpha-Synuclein/*metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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