MicroRNAs (miRNAs) represent a major system of post-transcriptional regulation, by either preventing translational initiation or by targeting messenger RNA transcripts for storage or degradation. miRNA deregulation has been reported in neurodegenerative disorders, such as Huntington’s disease (HD) and Parkinson’s disease (PD), which may impact gene expression and modify disease progression and/or severity. To assess the relationship of miRNA levels to HD, small RNA sequence analysis was performed for 26 HD and 36 non-disease control samples derived from human prefrontal cortex. 75 miRNAs were differentially expressed in HD brain as compared to controls at genome-wide significance (FDR q<0.05). Among HD brains, nine miRNAs were significantly associated with the extent of neuropathological involvement in the striatum and three of these significantly related to a continuous measure of striatal involvement, after statistical adjustment for the contribution of HD gene length. Five miRNAs were identified as having a significant, inverse relationship to age of motor onset, in particular, 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 levels to striatal involvement in the disease was independent of cortical involvement. In blood plasma from 26 HD, 4 asymptomatic HD gene carriers and 8 controls, miR-10b-5p levels were significantly elevated in HD as compared to non-diseased and preclinical HD subjects, demonstrating that miRNA alterations associated with diseased brain may be detected peripherally. Using small RNA sequence analysis for 29 PD brains, 125 miRNAs were identified as differentially expressed at genome-wide significance (FDR q<0.05) in PD versus controls. A set of 29 miRNAs accurately classified PD from non-diseased brain (93.9% specificity, 96.6% sensitivity, 4.8% absolute error). In contrast to HD, among PD cases, miR-10b-5p was significantly decreased and had a significant, positive association to onset age independent of age at death. These studies provide a detailed miRNA profile for HD and PD brain, identify miRNAs associated with disease pathology and suggest miRNA changes observed in brain can be detected in blood. Together, these findings support the potential of miRNA biomarkers for the diagnosis and assessment of progression for neurodegenerative diseases.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/14604 |
| Date | 17 February 2016 |
| Creators | Hoss, Andrew |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution-NonCommercial 4.0 International, http://creativecommons.org/licenses/by-nc/4.0/ |
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