T-test was used to determine significant differences between HD and control monkeys (P Value < 0.05 indicated by *). D) qPCR validation for the expression of 4 of the 5 miRNAs with significant Ingenuity analysis association to the HD pathway (miR-940 also showed association with the HD pathway, however, no Taqman assays were commercially available). Legend units: 1.0 = differs from median probe intensity by one log 2 unit (2-fold). Green squares represent lower than median levels of gene expression black squares represent median levels of gene expression red squares represent higher than median levels of gene expression. miRNA expression values (Log2 transformed & normalized microarray probe intensities) of the dysregulated microRNAs (P value < 0.05) in the HD and GFP control monkey cortex were median centered. C) Cluster diagram for dysregulated miRNAs in HD transgenic cortex. B) The fold change of HTT mRNA levels for the HD monkeys compared to the controls was quantitated by qPCR. The gDNA was amplified using specific primers for mHTT and the PCR product was analyzed by gel electrophoresis. A) Genomic DNA (gDNA) was isolated from the frontal cortex of 3 GFP control (C1-C3) and 8 HD monkeys (HD1-HD8).

Genotype and miRNA profiling analysis from HD monkey brains and human miR-128a expression. Additionally, we show that the miRNAs implicated in HD may regulate a significant network of genes within the HD canonical signaling pathway, providing a new paradigm approach for a disease with complex molecular dysregulation. We find that neuronally-enriched miRNAs may play a fundamental role in HD pathogenesis. Overall, we report miRNA dysregulation in the brains of HD monkeys, with parallel miRNA dysregulation in human patients. We expand on these datasets to show that miR-128a is downregulated in a cohort of both pre-symptomatic and post-symptomatic HD patients. Additionally, analysis of previously reported datasets revealed that miR-128a was also downregulated in the brain tissue of HD mice and humans. Interestingly, through bioinformatic analysis and subsequent in vitro studies, miR-128a was found to regulate the 3’-untranslated regions (3’ UTRs) of the HTT and Huntingtin Interacting Protein 1 ( HIP1) genes. We identified a significant dysregulation of 11 miRNAs in the HD monkeys and a correlation of their gene targets with the HD canonical signaling pathway. The HD monkeys examined in this study carry the exon 1 of human HTT gene with an expanded polyQ tract of 27Q – 122Q (Additional file 1: Table S1), a range well above the polyQ repeat of 10-11Q in wild-type (WT) rhesus macaque. Here we examine the miRNA expression profile of fetal and newborn frontal cortex from HD monkeys, with corresponding neuropathological analysis from a subset of those monkeys. MiRNA dysregulation has been reported in HD patients, transgenic HD mice, and in vitro experimental models. Published reports indicate that epigenetic factors, such as ncRNA regulation, work in union with the genetic anomalies to provoke pathogenic outcomes in HD. Although the causative factor for HD is monogenic and results from expansion in the polyglutamine (polyQ) region of the Huntingtin ( HTT) gene, there is wide variability in age of onset, polyQ length, and degree of symptoms. HD is characterized by progressive brain atrophy, particularly in the striatum and hippocampus, with associated deficits in cognitive, behavioral, and motor functions.

Indeed, the role of miRNA dysregulation in neurological diseases has come under increasingly intense study during recent years in the quest for novel therapeutic strategies. Modulation of miRNA activity has been associated with a broad scope of CNS disorders, including schizophrenia, autism, Fragile X, addiction, Parkinson’s Disease (PD), Alzheimer’s Disease (AD), Frontotemporal Dementia (FTD), and Huntington’s Disease (HD). Over the past decade, the microRNA (miRNA) class of noncoding RNAs (ncRNAs) has consistently been implicated in the neurogenesis, neurodegenerative, and synaptic plasticity functions of the central nervous system (CNS).

Hp 27q gamma control