Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of mouse cerebellum cells containing expanded or normal CAG trinucleotide repeats in the coding region for TATA-binding protein (TBP)

ABSTRACT: Transcription profiles were obtained for 2-month old mice containing an expanded or normal CAG trinucleotide repeat in the coding region for TATA-binding protein (TBP). Three different genotypes were used : TBP-13Q (normal), TBP-71Q (71 repeats), and TBP-105Q (105 repeats). Two lines of TBP-71Q (lines 16 and 27) were used in these experiments.

The 71Q and 105Q mice express a mutant version of the protein (TBP) and faithfully model the disease SCA17 (spinocerebellar ataxia-17, huntington disease-like 4, HDL4).

The constructs containing mixed CAG/CAA trinucleotide repeats (and encoding polyglutamine tracts) of variable length were made using a previously described method (Michalik A et al., Biotechniques, 2001). Briefly, synthetic CAG/CAA oligonucleotides were subcloned into a cDNA construct of the normal mouse (13 CAG/CAA) TBP gene. Because of the mixed nature of the repeat, its length is stable in mitotic and meiotic transmission.

ORGANISM(S): Mus musculus

SUBMITTER: Meyer Friedman

PROVIDER: E-MEXP-1313 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Polyglutamine domain modulates the TBP-TFIIB interaction: implications for its normal function and neurodegeneration.

Friedman Meyer J MJ Shah Anjali G AG Fang Zhi-Hui ZH Ward Elizabeth G EG Warren Stephen T ST Li Shihua S Li Xiao-Jiang XJ

Nature neuroscience 20071111 12

Expansion of the polyglutamine (polyQ) tract in human TATA-box binding protein (TBP) causes the neurodegenerative disease spinocerebellar ataxia 17 (SCA17). It remains unclear how the polyQ tract regulates normal protein function and induces selective neuropathology in SCA17. We generated transgenic mice expressing polyQ-expanded TBP. These mice showed weight loss, progressive neurological symptoms and neurodegeneration before early death. Expanded polyQ tracts reduced TBP dimerization but enhan ...[more]

PMID: 17994014

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Project description:Spinocerebellar ataxia type 3 (SCA3) is one of the polyglutamine (polyQ) diseases, which are caused by a CAG repeat expansion within the coding region of the associated genes. The CAG repeat specifies glutamine, and the expanded polyQ domain with mutation confers dominant toxicity on the protein. Traditionally, studies have focused on protein toxicity in polyQ disease mechanisms. Recent findings, however, demonstrate that the CAG repeat RNA, which encodes the toxic polyQ protein, also contributes to the disease in Drosophila. To provide insight into the nature of the RNA toxicity, we extracted brain-enriched RNA from flies expressing a toxic CAG repeat mRNA (CAG100) and a non-toxic interrupted CAA/G mRNA repeat (CAA/G105) for microarray analysis. This approach identified a set of genes that are differentially expressed specifically in CAG100 flies. Four independent replicates of flies expressing CAG0, CAG100, or CAA/G105 by elav-GAL4 were collected at 3 days. The transgenes are DsRed with either (CAG0) no CAG repeat in the 3'UTR, (CAG100) a CAG repeat of 100 CAGs in the 3'UTR, or (CAA/G105) an interrupted CAA CAG repeat in the 3'UTR (ref: Li et al., Nature 453:1107) The transgenes were adjusted to match in mRNA expression such that CAG0 flies had one copy of the transgene, CAG100 flies had 5 copies, and CAA/G105 had two copies. Fly brain tissue (about 20 brains per sample, dissected from head capsule, eyes, lamina and outer medulla removed) was dissected in cold phosphate buffered saline (PBS) and stored in Trizol reagent (Invitrogen Corporation, Carlsbad, CA) at -80Ë?C. Total brain RNA was extracted and purified using TRIzol reagent (Invitrogen) and the RNeasy Mini system (Qiagen), and treated with RNase-free DNase I (Qiagen). To define genes whose expression is altered in response to a toxic CAG repeat RNA, we compared CAG100 flies with age-matched flies expressing CAG0. To exclude transcriptional changes in response to a non-toxic trinucleotide repeat, a second gene list was generated by comparing CAA/G105 flies with age-matched CAG0 flies.

Project description:Huntington's disease (HD) is a neurodegenerative disorder typically diagnosed in mid-life that is caused by expansion of an otherwise polymorphic CAG trinucleotide repeat. The mutation causes a gain-of-function of the huntingtin protein to trigger a pathogenic process that produces detectable phenotypic differences many years before the traditional diagnosis, which is based upon characteristic motor symptoms. The prediagnosis phase of pathogenesis is now the subject of intense scrutiny by an NINDS-funded longitudinal study, PREDICT-HD, in which undiagnosed gene carriers are followed longitudinally and subjected to detailed phenotyping (PREDICT-HD Huntington Disease Study -- dbGaP Study Accession: <a href="./study.cgi?study_id=phs000222">phs000222</a>). This powerful approach, which offers the potential for moving the focus of therapeutic development to the decades prior to neurological disease diagnosis, is enabled by the fact that all individuals with HD have the same type of mutation, which can be determined at any time in life by a single HD CAG repeat PCR amplification assay. The precise length of the HD CAG repeat differs between individuals. There is a strong negative correlation between the number of CAG repeats and the age at onset of diagnostic neurological abnormalities in HD, such that the CAG repeat accounts for ~50% of the variation in age at diagnosis. Analysis of the remaining variance not explained by the length of the CAG repeat has shown that it is highly heritable, being due to genetic variation, elsewhere in the genome. The intent of the Genetic Modifiers of Huntington's Disease study is to identify genetic modifiers of HD pathogenesis by using genomewide association techniques in diagnosed HD individuals to identify genetic factors associated with the residual variance in age at onset not explained by the CAG repeat, and to extend these analyses to pre-diagnosis phenotypes, for example, those defined in the PREDICT-HD study. Identification of modifier genes is a top priority for HD research (and an example of an approach that can be applied in other late-onset genetic disorders), as it could provide clues to developing rational treatments that delay or prevent the pathogenic process from causing the ravages of the disease that ensue in the ~15 years of inexorable decline to ultimate death that now follows clinical diagnosis. To further that goal, the release of study version 2 makes available whole exome sequencing data of n=221 study participants.

Dataset Information

Transcription profiling of mouse cerebellum cells containing expanded or normal CAG trinucleotide repeats in the coding region for TATA-binding protein (TBP)

Publications

Polyglutamine domain modulates the TBP-TFIIB interaction: implications for its normal function and neurodegeneration.

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