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microRNA-128a dysregulation in transgenic Huntington's disease monkeys
Jannet Kocerha, Yan Xu, Melinda S Prucha
1Division of Neuropharmacology and Neurologic Disease, Yerkes National Primate Research Center, 954 Gatewood Rd,, N,E Atlanta, GA 30329, USA. awchan@emory.edu.
Background:
Huntington'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.
Results:
In 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).
Conclusion:
Our 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.
Insights
MicroRNAs (miRNAs) are implicated in Huntington's Disease (HD). This study found miR-128a downregulation in HD monkeys and patients, suggesting its role in HD pathogenesis and potential as a therapeutic target.
Area of Science:
- Neuroscience
- Genetics
- Epigenetics
Background:
- Huntington's Disease (HD) is a progressive neurodegenerative disorder caused by a mutation in the Huntingtin (HTT) gene.
- The role of microRNAs (miRNAs) in HD pathogenesis is not well understood.
- This study investigates miRNA dysregulation in a primate model of HD.
Purpose of the Study:
- To examine miRNA dysregulation in transgenic Huntington's Disease monkeys.
- To identify specific miRNAs associated with HD pathogenesis.
- To investigate the role of miR-128a in HD.
Main Methods:
- Analysis of miRNA expression in the frontal cortex of transgenic HD monkeys.
- Focus on miR-128a due to its known association with HD in humans and mice.
- Confirmation of miR-128a levels in HD patient brains (pre- and post-symptomatic).
- Identification of miR-128a target genes involved in HD signaling.
Main Results:
- Eleven miRNAs were significantly associated with HD in the HD monkey model.
- miR-128a was downregulated in HD monkeys at birth.
- miR-128a downregulation was confirmed in pre- and post-symptomatic HD patients.
- miR-128a regulates key HD signaling genes, including HTT and HIP1.
Conclusions:
- miR-128a may play a critical role in the pathogenesis of Huntington's Disease.
- miR-128a is a potential therapeutic target for HD.
- miR-128a could serve as a biomarker for Huntington's Disease.
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