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miR-10b-5p expression in Huntington's disease brain relates to age of onset and the extent of striatal involvement.
BMC Med Genomics. 2015 Mar 01; 8:10.BM

Abstract

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.

Authors+Show Affiliations

Department of Neurology, Boston University School of Medicine, Boston, MA, USA. andyhoss@bu.edu. Graduate Program in Genetics and Genomics, Boston University School of Medicine, Boston, MA, USA. andyhoss@bu.edu.Department of Neurology, Boston University School of Medicine, Boston, MA, USA. labadorf@bu.edu. Bioinformatics Program, Boston University, Boston, MA, USA. labadorf@bu.edu.Department of Neurology, Boston University School of Medicine, Boston, MA, USA. jlatoure@bu.edu.Bioinformatics Program, Boston University, Boston, MA, USA. vkartha@bu.edu.Department of Neurology, Boston University School of Medicine, Boston, MA, USA. tmassood@gmail.com.Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. gusella@helix.mgh.harvard.edu.Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. macdonam@helix.mgh.harvard.edu.Department of Neurology, Boston University School of Medicine, Boston, MA, USA. chenjf@bu.edu.Friedman Brain Institute, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA. schahram.akbarian@mssm.edu.Program in Bioinformatics and Integrative Biology, and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA. zhiping.weng@umassmed.edu.Department of Pathology and Cell Biology, Columbia University Medical Center and the New York Presbyterian Hospital, New York, NY, USA. jgv2001@cumc.columbia.edu.Department of Neurology, Boston University School of Medicine, Boston, MA, USA. rmyers@bu.edu. Genome Science Institute, Boston University School of Medicine, Boston, MA, USA. rmyers@bu.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25889241

Citation

Hoss, Andrew G., et al. "MiR-10b-5p Expression in Huntington's Disease Brain Relates to Age of Onset and the Extent of Striatal Involvement." BMC Medical Genomics, vol. 8, 2015, p. 10.
Hoss AG, Labadorf A, Latourelle JC, et al. MiR-10b-5p expression in Huntington's disease brain relates to age of onset and the extent of striatal involvement. BMC Med Genomics. 2015;8:10.
Hoss, A. G., Labadorf, A., Latourelle, J. C., Kartha, V. K., Hadzi, T. C., Gusella, J. F., MacDonald, M. E., Chen, J. F., Akbarian, S., Weng, Z., Vonsattel, J. P., & Myers, R. H. (2015). MiR-10b-5p expression in Huntington's disease brain relates to age of onset and the extent of striatal involvement. BMC Medical Genomics, 8, 10. https://doi.org/10.1186/s12920-015-0083-3
Hoss AG, et al. MiR-10b-5p Expression in Huntington's Disease Brain Relates to Age of Onset and the Extent of Striatal Involvement. BMC Med Genomics. 2015 Mar 1;8:10. PubMed PMID: 25889241.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - miR-10b-5p expression in Huntington's disease brain relates to age of onset and the extent of striatal involvement. AU - Hoss,Andrew G, AU - Labadorf,Adam, AU - Latourelle,Jeanne C, AU - Kartha,Vinay K, AU - Hadzi,Tiffany C, AU - Gusella,James F, AU - MacDonald,Marcy E, AU - Chen,Jiang-Fan, AU - Akbarian,Schahram, AU - Weng,Zhiping, AU - Vonsattel,Jean Paul, AU - Myers,Richard H, Y1 - 2015/03/01/ PY - 2014/10/28/received PY - 2015/02/06/accepted PY - 2015/4/19/entrez PY - 2015/4/19/pubmed PY - 2016/1/30/medline SP - 10 EP - 10 JF - BMC medical genomics JO - BMC Med Genomics VL - 8 N2 - 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. SN - 1755-8794 UR - https://www.unboundmedicine.com/medline/citation/25889241/miR_10b_5p_expression_in_Huntington's_disease_brain_relates_to_age_of_onset_and_the_extent_of_striatal_involvement_ DB - PRIME DP - Unbound Medicine ER -