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Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
MicroRNA-27a reduces mutant hutingtin aggregation in an in vitro model of Huntington's disease
Jae-Jun Ban1, Jin-Young Chung2, Mijung Lee1
1Department of Neurology, Seoul National University Hospital, Seoul, South Korea.
Abstract:
Huntington's disease (HD) is a fatal genetic disease caused by abnormal aggregation of mutant huntingtin protein (mHtt). Reduction of mHtt aggregation decreases cell death of the brain and is a promising therapeutic strategy of HD. MicroRNAs are short non-coding nucleotides which modulate various genes and dysregulated in many diseases including HD. MicroRNA miR-27a was reported to be reduced in the brain of R6/2 HD mouse model and modulate multidrug resistance protein-1 (MDR-1). Using subventricular zone-derived neuronal stem cells (NSCs), we used in vitro HD model to test the effect of miR-27a on MDR-1 and mHtt aggregation. R6/2-derived NSCs can be differentiated under condition of growth factor deprivation, and the progression of differentiation leads to a decrease of MDR-1 level and efflux function of cells. Immunocytochemistry result also confirmed that mHtt aggregation was increased with differentiation. We transfected miR-27a in the R6/2-derived differentiated NSCs, and examined phenotype of HD, mHtt aggregation. As a result, miR-27a transfection resulted in reduction of mHtt aggregation in HD cells. In addition, MDR-1, which can transport mHtt, protein level was increased by miR-27a transfection. Conversely, knock-down of MDR-1 through MDR-1 siRNA increased mHtt aggregation in vitro. Our results indicate that miR-27a could reduce mHtt level of the HD cell by augmenting MDR-1 function.
Insights
MicroRNA miR-27a reduces mutant huntingtin (mHtt) aggregation in Huntington's disease (HD) cells by increasing multidrug resistance protein-1 (MDR-1). This suggests miR-27a as a potential therapeutic target for HD.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington's disease (HD) is a fatal neurodegenerative disorder caused by the aggregation of mutant huntingtin protein (mHtt).
- MicroRNAs (miRNAs) are key regulators of gene expression, and their dysregulation is implicated in HD pathogenesis.
- miR-27a is downregulated in HD models and has been linked to multidrug resistance protein-1 (MDR-1), a transporter protein.
Purpose of the Study:
- To investigate the role of miR-27a in an in vitro model of Huntington's disease using neuronal stem cells (NSCs).
- To determine the effect of miR-27a on mHtt aggregation and MDR-1 expression in HD-model NSCs.
- To explore the therapeutic potential of modulating miR-27a for HD.
Main Methods:
- Utilized an in vitro HD model with R6/2-derived NSCs differentiated under growth factor deprivation.
- Transfected miR-27a into differentiated HD NSCs and assessed mHtt aggregation and MDR-1 levels.
- Investigated the impact of MDR-1 knockdown using siRNA on mHtt aggregation.
Main Results:
- miR-27a transfection reduced mHtt aggregation in differentiated HD NSCs.
- miR-27a transfection increased MDR-1 protein levels, enhancing its efflux function.
- Knockdown of MDR-1 exacerbated mHtt aggregation in vitro.
Conclusions:
- miR-27a plays a protective role in HD by reducing mHtt aggregation.
- Augmenting MDR-1 function via miR-27a is a potential therapeutic strategy for Huntington's disease.
- Further research into miR-27a and MDR-1 interactions could yield novel HD treatments.
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