The relationship of microRNAs to clinical features of Huntington's and Parkinson's disease
Hoss_bu_0017E_11703.pdf (1.881Mb) Main dissertation
Hoss_bu_0017E_429/Table S52.pdf (407.1Kb) Results from miRNA differential expression analysis in Parkinson’s disease.
Hoss_bu_0017E_429/Table S51.pdf (29.51Kb) Detailed sample information.
Hoss_bu_0017E_429/Table S31.pdf (24.50Kb) Sample information for 36 control brains used for miRNA- sequencing.
Hoss_bu_0017E_429/Table S32.pdf (28.94Kb) Sample information for 28 Huntington’s disease brains used for miRNA-sequencing.
Hoss_bu_0017E_429/Table S33.pdf (34.70Kb) Read statistics for miRNA-sequence analysis.
Hoss_bu_0017E_429/Table S34.pdf (32.59Kb) Correlation of differentially expressed miRNA precursor pairs.
Hoss_bu_0017E_429/Table S35.pdf (22.32Kb) Summary statistics for Firefly BioWorks assay.
Hoss_bu_0017E_429/Table S36.pdf (35.33Kb) Linear regression analysis modeled the relationship of miRNA expression and Vonsattel grade.
Hoss_bu_0017E_429/Table S28.pdf (30.13Kb) Read statistics for mRNA-sequence analysis.
Hoss_bu_0017E_429/Table S27.pdf (36.14Kb) Mean and standard deviation inner-distance estimates for TopHat2 alignment.
Hoss_bu_0017E_429/Table S26.pdf (30.77Kb) Read statistics for miRNA-sequence analysis.
Hoss_bu_0017E_429/Table S25.pdf (27.82Kb) Sample information for fourteen Parkinson's disease brains used for RT-qPCR replication study.
Hoss_bu_0017E_429/Table S24.pdf (24.72Kb) miRNA RT-qPCR replication study results.
Hoss_bu_0017E_429/Table S23.pdf (30.12Kb) Sample information for eight control brains used for RT-qPCR replication study.
Hoss_bu_0017E_429/Table S22.pdf (28.99Kb) Sample information for eight Huntington's disease brains used for RT-qPCR replication study.
Hoss_bu_0017E_429/Table S21.pdf (24.88Kb) miRNA RT-qPCR validation study results.
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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.