miR-10b-5p expression in Huntington’s disease brain relates to age of onset and the extent of striatal involvement

BMC Medical Genomics

Richard H Myers⁷  Jean Paul Vonsattel⁵  Zhiping Weng⁶  Schahram Akbarian¹  Jiang-Fan Chen³  Marcy E MacDonald²  James F Gusella²  Tiffany C Hadzi³  Vinay K Kartha⁸  Jeanne C Latourelle³  Adam Labadorf⁸  Andrew G Hoss⁴ 

[1] Friedman Brain Institute, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA;Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA;Department of Neurology, Boston University School of Medicine, Boston, MA, USA;Graduate Program in Genetics and Genomics, Boston University School of Medicine, Boston, MA, USA;Department of Pathology and Cell Biology, Columbia University Medical Center and the New York Presbyterian Hospital, New York, NY, USA;Program in Bioinformatics and Integrative Biology, and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA;Genome Science Institute, Boston University School of Medicine, Boston, MA, USA;Bioinformatics Program, Boston University, Boston, MA, USA

关键词: Neuropathological involvement;    Age at onset;    RNA biology;    miRNA;    microRNA;    miRNA-sequencing;    Striatum;    Prefrontal cortex;    Human;    Huntington’s disease;   

Others  :  1137819
DOI  :  10.1186/s12920-015-0083-3

 received in 2014-10-28, accepted in 2015-02-06,  发布年份 2015

【 摘 要 】

Background

MicroRNAs (miRNAs) are small non-coding RNAs that recognize sites of complementarity of target messenger RNAs, resulting in transcriptional regulation and translational repression of target genes. In Huntington’s disease (HD), a neurodegenerative disease caused by a trinucleotide repeat expansion, miRNA dyregulation has been reported, which may impact gene expression and modify the progression and severity of HD.

Methods

We performed next-generation miRNA sequence analysis in prefrontal cortex (Brodmann Area 9) from 26 HD, 2 HD gene positive, and 36 control brains. Neuropathological information was available for all HD brains, including age at disease onset, CAG-repeat size, Vonsattel grade, and Hadzi-Vonsattel striatal and cortical scores, a continuous measure of the extent of neurodegeneration. Linear models were performed to examine the relationship of miRNA expression to these clinical features, and messenger RNA targets of associated miRNAs were tested for gene ontology term enrichment.

Results

We identified 75 miRNAs differentially expressed in HD brain (FDR q-value <0.05). Among the HD brains, nine miRNAs were significantly associated with Vonsattel grade of neuropathological involvement and three of these, miR-10b-5p, miR-10b-3p, and miR-302a-3p, significantly related to the Hadzi-Vonsattel striatal score (a continuous measure of striatal involvement) after adjustment for CAG length. Five miRNAs (miR-10b-5p, miR-196a-5p, miR-196b-5p, miR-10b-3p, and miR-106a-5p) were identified as having a significant relationship to CAG length-adjusted age of onset including miR-10b-5p, the mostly strongly over-expressed miRNA in HD cases. Although prefrontal cortex was the source of tissue profiled in these studies, the relationship of miR-10b-5p expression to striatal involvement in the disease was independent of cortical involvement. Correlation of miRNAs to the clinical features clustered by direction of effect and the gene targets of the observed miRNAs showed association to processes relating to nervous system development and transcriptional regulation.

Conclusions

These results demonstrate that miRNA expression in cortical BA9 provides insight into striatal involvement and support a role for these miRNAs, particularly miR-10b-5p, in HD pathogenicity. The miRNAs identified in our studies of postmortem brain tissue may be detectable in peripheral fluids and thus warrant consideration as accessible biomarkers for disease stage, rate of progression, and other important clinical characteristics of HD.

【 授权许可】

   
2015 Hoss et al.; licensee BioMed Central.

【 图 表 】

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