Abstract
BackgroundHuntington’s Disease (HD) is a progressive neurodegenerative disorder with a single causal mutation in the Huntingtin (HTT) gene. MicroRNAs (miRNAs) have recently been implicated as epigenetic regulators of neurological disorders, however, their role in HD pathogenesis is not well defined. Here we study transgenic HD monkeys (HD monkeys) to examine miRNA dysregulation in a primate model of the disease.ResultsIn this report, 11 miRNAs were found to be significantly associated (P value < 0.05) with HD in the frontal cortex of the HD monkeys. We further focused on one of those candidates, miR-128a, due to the corresponding disruption in humans and mice with HD as well as its intriguing lists of gene targets. miR-128a was downregulated in our HD monkey model by the time of birth. We then confirmed that miR-128a was also downregulated in the brains of pre-symptomatic and post-symptomatic HD patients. Additionally, our studies confirmed a panel of canonical HD signaling genes regulated by miR-128a, including HTT and Huntingtin Interaction Protein 1 (HIP1).ConclusionOur studies found that miR-128a may play a critical role in HD and could be a viable candidate as a therapeutic or biomarker of the disease.
Highlights
Huntington’s Disease (HD) is a progressive neurodegenerative disorder with a single causal mutation in the Huntingtin (HTT) gene
Modulation of miRNA activity has been associated with a broad scope of central nervous system (CNS) disorders, including schizophrenia, autism, Fragile X, addiction, Parkinson’s Disease (PD), Alzheimer’s Disease (AD), Frontotemporal Dementia (FTD), and Huntington’s Disease (HD) [10,11,12,13,14,15,16,17]
Genotyping and mRNA expression analysis of HD monkeys Genomic DNA isolated from all the control and HD monkeys was analyzed by PCR for detection of the mutant HTT (mHTT) transgene
Summary
Huntington’s Disease (HD) is a progressive neurodegenerative disorder with a single causal mutation in the Huntingtin (HTT) gene. We study transgenic HD monkeys (HD monkeys) to examine miRNA dysregulation in a primate model of the disease. MiRNA dysregulation has been reported in HD patients, transgenic HD mice, and in vitro experimental models [22,23,24,25,26,27,28]. Analysis of previously reported datasets revealed that miR-128a was downregulated in the brain tissue of HD mice and humans [22,23,24,25]. We expand on these datasets to show that miR-128a is downregulated in a cohort of both pre-symptomatic and post-symptomatic HD patients
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