miR-10b-5p expression in Huntington's disease brain relates to age of onset and the extent of striatal involvement
AuthorsHoss, Andrew G.
Latourelle, Jeanne C.
Kartha, Vinay K.
Hadzi, Tiffany C.
Gusella, James F.
MacDonald, Marcy E.
Vonsattel, Jean Paul
Myers, Richard H.
UMass Chan AffiliationsDepartment of Biochemistry and Molecular Pharmacology
Program in Bioinformatics and Integrative Biology
Document TypeJournal Article
KeywordsBiochemistry, Biophysics, and Structural Biology
Genetics and Genomics
MetadataShow full item record
AbstractBACKGROUND: 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.
SourceBMC Med Genomics. 2015 Mar 1;8:10. doi: 10.1186/s12920-015-0083-3. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/25903
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Except where otherwise noted, this item's license is described as © 2015 Hoss et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<a href="http://creativecommons.org/licenses/by/4.0">http://creativecommons.org/licenses/by/4.0</a>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (<a href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</a>) applies to the data made available in this article, unless otherwise stated.