Functional Gene Expression Profiling in Yeast Implicates Translational Dysfunction in Mutant Huntingtin Toxicity
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Functional Gene Expression Profiling in Yeast Implicates Translational Dysfunction in Mutant Huntingtin Toxicity*
Huntington disease (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine tract in the huntingtin (htt) protein. To uncover candidate therapeutic targets and networks involved in pathogenesis, we integrated gene expression profiling and functional genetic screening to identify genes critical for mutant htt toxicity in yeast. Using mRNA profiling, we have identified gene...
متن کاملAmyloid-Mediated Sequestration of Essential Proteins Contributes to Mutant Huntingtin Toxicity in Yeast
BACKGROUND Polyglutamine expansion is responsible for several neurodegenerative disorders, among which Huntington disease is the most well-known. Studies in the yeast model demonstrated that both aggregation and toxicity of a huntingtin (htt) protein with an expanded polyglutamine region strictly depend on the presence of the prion form of Rnq1 protein ([PIN+]), which has a glutamine/asparagine...
متن کاملSerine 421 regulates mutant huntingtin toxicity and clearance in mice.
Huntington's disease (HD) is a progressive, adult-onset neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the N-terminal region of the protein huntingtin (HTT). There are no cures or disease-modifying therapies for HD. HTT has a highly conserved Akt phosphorylation site at serine 421, and prior work in HD models found that phosphorylation at S421 (S421-P) diminishes the t...
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The Huntington's disease (HD) CAG repeat, encoding a polymorphic glutamine tract in huntingtin, is inversely correlated with cellular energy level, with alleles over approximately 37 repeats leading to the loss of striatal neurons. This early HD neuronal specificity can be modeled by respiratory chain inhibitor 3-nitropropionic acid (3-NP) and, like 3-NP, mutant huntingtin has been proposed to ...
متن کاملYeast Genes That Enhance the Toxicity of a Mutant Huntingtin Fragment or -Synuclein
Genome-wide screens were performed in yeast to identify genes that enhance the toxicity of a mutant huntingtin fragment or of -synuclein. Of 4850 haploid mutants containing deletions of nonessential genes, 52 were identified that were sensitive to a mutant huntingtin fragment, 86 that were sensitive to -synuclein, and only one mutant that was sensitive to both. Genes that enhanced toxicity of t...
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ژورنال
عنوان ژورنال: Journal of Biological Chemistry
سال: 2011
ISSN: 0021-9258
DOI: 10.1074/jbc.m110.101527