by Yusuf Issa Olakunle, M.Sc and Shang-Hsun Yang, Ph.D.
Department of Physiology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
Huntington’s disease (HD)
HD is a human inheritable autosomal dominant disease, and this disease is caused by a mutation of CAG trinucleotide repeats in exon 1 region of Huntingtin (HTT) gene (1993). In principle, the longer of CAG trinucleotide repeats, the more severe the HD. As a result, expression of mutant HTT leads to toxic gain-of-function, forming cytotoxicity inside cells (Li and Li 2004, Yang and Chan 2011). In addition, the size of HTT fragment is also a critical factor affecting HD. Due to proteolysis of full-length HTT, different N-terminal HTT fragments are generated. As smaller N-terminal HTT fragments carry longer CAG trinucleotide repeats, earlier onset and more severe symptoms of HD will be observed(Schilling et al. 1999). Typically pathological characteristics of HD include nuclear aggregates, intranuclear aggregates and neuropil aggregates, which are detected in central nervous system (CNS) of HD patients and animal models (Li and Li 2004, Yang et al. 2008). Clinical symptoms of HD comprise cognitive dysfunction, emotional changes, mental deterioration, motor deficits, chorea and dystonia (Yang and Chan 2011, Bates et al. 2015). Up to date, there is no cure for this genetic disease, resulting in that HD patients suffer unimaginable pain till death.
microRNA in Huntington’s disease
Mutant HTT involves in abnormal gene regulation, and results in pathological symptoms in HD patients and animals (Yang and Chan 2011, Bates et al. 2015), suggesting the important role of HTT in gene regulatory mechanisms. Recently, post-transcriptional regulation of non-coding RNAs, especially microRNAs (miRNAs), has been extensively studied in the field of gene regulation in neuronal diseases. miRNAs are small nucleotides, and involved in several cellular processes and biological functions, such as growth, development, differentiation, proliferation and apoptosis. Most miRNAs are evolutionarily conserved with their sequences among different organisms, and the evolutionary presence of multicellular organisms appears to correlate with the appearance of the miRNA pathway for regulation of gene expression. In HD, first miRNA study was reported in 2008, and showed that higher expression of Repressor Element 1 Silencing Transcription Factor (REST) enhanced the repression of miR-132 in the brain of HD mice and patients (Johnson et al. 2008). Targeting to REST complex, miR-9 and miR-9* also influence severity of HD in patients (Packer et al. 2008). Later, miR-146a and miR-34b were reported to involve in the gene regulation and pathogenesis of HD as well (Sinha et al. 2010, Gaughwin et al. 2011). These studies suggest miRNA-mediated pathway should contribute to this neurodegenerative disease, and alteration of certain miRNAs might provide beneficial effects on the progression of HD.
In our current studies, we showed the beneficial effects of one specific miRNA, miR-196a, on HD via cell, transgenic mouse and HD patient-derived induced pluripotent stem cell (HD-iPSC) models (Cheng et al. 2013). miR-196a not only ameliorated the molecular and pathological phenotypes, but also improved the behavioral symptoms in HD transgenic mice. Especially, these effects have also been confirmed in the unique model of differentiated neurons from HD-iPSCs. Similarly, an independent study by Kunkanjanawan and his colleagues also found that overexpression of miR-196a in neural progenitor cells of HD non-human primate (HD-NHP) and HD differentiated neural cells (HD-NCs) improved mutant HTT induced cytotoxicity and apoptosis (Kunkanjanawan et al. 2016). These results imply that manipulating miR-196a might provide beneficial effects through certain unknown mechanisms of neuron protection in HD.
A potential role of mrR-196a for neuroprotection
In our previous study, we predict miR-196a might putatively provide the neuroprotective functions in HD through the regulation of neuronal morphology (Fu et al. 2015). Neuronal morphology is one of important effects, and influences intracellular trafficking, synaptic development, plasticity and brain circuitry, further affecting motor, memory and cognitive functions in brain (Skaper 2005, Calabrese 2008, Olde Loohuis et al. 2012, Bencsik et al. 2015). In addition, neuronal morphology is highly regulated by gene expression, and several important genes, such as nuclear respiratory factor 1, integrin-associated protein and synapsin I, have been shown to involve in this mechanism (Calabrese 2008, Tong et al. 2013). These regulatory factors may enhance the cytoskeleton, growth cones or neurite branching of neuronal cells during development, leading to establishment of functional neurons. As described above, miRNAs also involve in regulation of neuronal morphology during the progression of neuronal development (Schratt et al. 2006). Since miRNAs may affect several direct target genes simultaneously, it suggests the complicated regulation of neuronal morphology through mechanisms of miRNAs.
In conclusion, miRNA is still a new field in HD, but it may be at proof-of concept stage in laboratories, suggesting there is a long way to go. However, we believe these miRNA regulatory mechanisms targeting several genes simultaneously may provide an alternative insight for the therapeutical strategy for HD. Especially, it will be interesting to understand the mechanisms of certain specific miRNAs, such as miR-196a, to provide neuroprotective effects. With these related studies to understand between miRNAs and HD, we hope it will facilitate the development of potential therapy using miRNAs for this devastating HD, even for other neuronal diseases.
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About the Authors
Yusuf Issa Olakunle is a PhD student in Taiwan International Graduate Program (TIGP) of the Neuroscience at National Cheng Kung University (NCKU). He obtained the B.Sc. degree in Physiology from Ahmadu Bello University, Zaria, Nigeria, in 2010, and M.Sc. degree in Physiology from the University of Ibadan, Nigeria, in 2014. He currently conducts his research works in Dr. Yang’s laboratory, and demonstrates on the therapeutic roles of miR-196a in Huntington’s disease (HD).
Dr. Shang-Hsun Yang is the Associate Professor in Department of Physiology at NCKU, Taiwan. He received his B.Sc. degree at National Chung Hsing University in 1998, M.Sc. degree at National Taiwan University in 2000 and Ph.D. degree at Emory University, USA, in 2008. He has developed his own research career at NCKU since 2009. His research interests focus on the regulation of microRNAs on HD, and tries to understand the regulatory mechanisms and potentially therapeutic directions for this neurodegenerative disease. Additionally, he also attempts to expand his research fields to other neurodegenerative diseases, and hopes to demonstrate the relationship between specific microRNAs and neurodegenerative diseases.