Dataset Information

Huntington's disease brain-derived small RNAs recapitulate associated neuropathology in mice [Mouse RNA-seq]

ABSTRACT: Progressive motor alterations and selective death of striatal medium spiny neurons (MSNs) are key pathological hallmarks of Huntington's disease (HD), a neurodegenerative condition caused by a CAG trinucleotide repeat expansion in the coding region of the huntingtin (HTT) gene. Most research has focused on the pathogenic effects of the resultant protein product(s); however, growing evidence indicates that expanded CAG repeats within mutant HTT mRNA and derived small CAG repeat RNAs (sCAG) participate in HD pathophysiology. The individual contribution of protein versus RNA toxicity to HD pathophysiology remains largely uncharacterized and the role of other classes of small RNAs (sRNA) that are strongly perturbed in HD is uncertain. Here, have injected vehicle (VEH), CTL-sRNA-PT (obtained from the putamen of non-affected individuals) or HD-sRNA-PT (obtained from the putamen of patients with HD) into the striatum of wild type (WT) mice, and demonstrate that sRNA produced in the putamen and cortex of HD patients are sufficient to induce HD pathology in vivo, including transcriptional alterations. To reveal the transcriptional changes produced by sCAG, we co-injected human sRNAs with a locked nucleic acid (LNA) modified anti-sense oligonucleotide complementary to sCAG (HD-sRNA-PT + LNA-CTG) or an analogous scrambled LNA (HD-sRNA-PT + LNA-SCB). We have performed mRNA-seq in the different experimental groups: Vehicle, CTL-sRNA-PT, HD-sRNA-PT, HD-sRNA-PT + LNA-CTG, and HD-sRNA-PT + LNA-SCB. Here we describe the procedure to obtain and sequence human sRNA dataset isolated from the different brain areas.

ORGANISM(S): Mus musculus

PROVIDER: GSE165658 | GEO | 2021/02/16

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:In Huntington’s disease (HD), expanded HTT CAG repeat length correlates strongly with age at motor onset, indicating that it determines the rate of the disease process leading to diagnostic clinical manifestations. Similarly, in normal individuals, HTT CAG repeat length is correlated with biochemical differences that reveal it as a functional polymorphism. Here, we tested the hypothesis that gene expression signatures can capture continuous, length-dependent effects of the HTT CAG repeat. Using gene expression datasets for 107 HD and control lymphoblastoid cell lines, we constructed mathematical models in an iterative manner, based upon CAG correlated gene expression patterns in randomly chosen training samples, and tested their predictive power in test samples. Predicted CAG repeat lengths were significantly correlated with experimentally determined CAG repeat lengths, whereas models based upon randomly permuted CAGs were not at all predictive. Predictions from different batches of mRNA for the same cell lines were significantly correlated, implying that CAG length-correlated gene expression is reproducible. Notably, HTT expression was not itself correlated with HTT CAG repeat length. Taken together, these findings confirm the concept of a gene expression signature representing the continuous effect of HTT CAG length and not primarily dependent on the level of huntingtin expression. Such global and unbiased approaches, applied to additional cell types and tissues, may facilitate the discovery of therapies for HD by providing a comprehensive view of molecular changes triggered by HTT CAG repeat length for use in screening for and testing compounds that reverse effects of the HTT CAG expansion. To evaluate the continuous analytical approach as a strategy to discover the molecular consequences of the HTT CAG repeat, genome-wide gene expression datasets were generated from a panel of 107 human lymphoblastoid cell lines with HTT CAGs spanning the entire spectrum of allele sizes.

Dataset Information

Huntington's disease brain-derived small RNAs recapitulate associated neuropathology in mice [Mouse RNA-seq]

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets