MicroRNA (miRNA) is a non-coding single-stranded small molecule of approximately 21 nucleotides. It degrades or inhibits the translation of RNA by targeting the 3′-UTR. The miRNA plays an important role in the growth, development, differentiation, and functional execution of the nervous system. Dysregulated miRNA expression has been associated with several pathological processes of neurodegenerative disorders, including Huntington’s disease (HD). Recent studies have suggested promising roles of miRNAs as biomarkers and potential therapeutic targets for HD. Here, we review the emerging role of dysregulated miRNAs in HD and describe general biology of miRNAs, their pathophysiological implications, and their potential roles as biomarkers and therapeutic agents.
Huntington’s disease (HD) is a neurodegenerative disorder caused by abnormal amplification of CAG sequences in the Huntingtin (Htt) gene on chromosome 4. This results in the production of a mutant huntingtin (mHTT) protein with an abnormally long polyglutamine repeat (Jacobsen et al., 2010). The pathogenic gene, Htt, located on chromosome 4p16.3 and was identified in 1993 (Bates et al., 2015). HD is related to the unstable expansion of CAG triplet repeats in exon 1 of Htt. The normal Htt allele contains 6–35 CAG triplet repeats. CAG triplet expansion of 40 repeats or more is abnormal and complete penetration. Alleles with 36–39 CAG repeats are considered to have lower penetrance. Although the 27–35 CAG repeats are within the normal range, they are considered to be intermediate or unstable alleles that may extend or contract during reproduction. The main clinical symptoms of HD are usually classified into three categories: motor symptoms, psychiatric disorders, and cognitive dysfunction (Sheikh and Guerciolini, 2019). The typical dyskinesia of the disease is chorea-like involuntary movement. Approximately 90% of patients with HD experience this typical dyskinesia, but most of the patients’ motor symptoms are a combination of various dyskinesias, including chorea-like symptoms, dystonia, ataxia, and Parkinson’s syndrome (Heo and Scott, 2017). Psychiatric symptoms in patients with HD may appear earlier than dyskinesia, and patients may also experience anxiety and irritability (Goh et al., 2018). In addition, the cognitive impairment of HD is mainly executive dysfunction, and some studies have shown that the cognitive impairment could be worsen with the increase in the repeat length of the CAGs and the patient’s age (Bayliss et al., 2019).
Currently, the molecular mechanism of HD remains unclear; however, there are two main hypothesis: wild-type Htt (wtHtt) loss-of-function and mutant Htt (mHtt) gain-of-toxicity (Tellone et al., 2019). The wtHtt plays an important role in embryonic development; it is antiapoptotic, regulates gene transcription in neurons and synaptic transmission, and promotes vesicle transport function (Romo et al., 2018; Orozco-Diaz et al., 2019; Smith-Dijak et al., 2019). The loss of the normal physiological functions of wtHtt is involved in the pathogenesis of HD. The mHtt also produces additional toxic pathogenic effects, including adverse effects on apoptosis, gene transcription, axonal transport, synaptic transmission, the ubiquitin-proteasome system, and calcium ion signal transduction (Hamilton et al., 2019; Wanker et al., 2019). Although the precise mechanisms underlying HD pathogenesis have not yet been fully elucidated, it is known that transcriptional dysregulation is associated with this disease. Thus, the regulation of transcriptional regulators has been considered to be a key pathogenic mechanism in HD (Tabrizi et al., 2019).
Although some breakthroughs have been made in the study of HD pathogenesis, there is still a lack of effective approaches to treat HD. Currently, empirical symptomatic supportive therapy is the main treatment method. Antipsychotic drugs such as butbenazine or olanzapine can be used to control the chorea. Antidepressants may improve the symptoms of depression, and psychotherapy is mainly expected to alleviate cognitive dysfunction. However, these therapeutic strategies failed to meet clinical expectations (Fritz et al., 2017). Induction of mutant IT-15 gene silencing therapy can fundamentally reduce the formation of the mHTT protein to achieve the therapeutic effect. Non-specific partial inhibition of wtHtt and mHtt gene expression was effective in animals with HD, and no apparent adverse effects were detected. However, potential safety risks could not be ruled out after application in humans (Wild and Tabrizi, 2017). The optimal treatment strategy is to target specific alleles for gene interference, which selectively inhibit the expression of the mHtt gene but have no effect on the wtHtt gene (Shannon, 2020).
MicroRNAs (miRNAs) are a class of evolutionarily conserved endogenous non-coding short RNAs. By binding to the 3′ untranslated region (UTR) of the target mRNA, the expression activity of the target gene is negatively regulated by miRNAs at the post-transcriptional level to inhibit the translation or degradation of the target mRNA (Tafrihi and Hasheminasab, 2019). The miRNAs regulate the expression of approximately 90% of genes in the body and are involved in cell proliferation, development, and senescence (Ying et al., 2018). Studies have shown that miRNAs are involved in the early differentiation, development, and function of neurons (De Pietri Tonelli et al., 2008). Targeted regulation of specific miRNA expression may provide new hope for the treatment of HD. Previous studies have shown that miR-9/miR-9 significantly decreased in the brain during the progression of HD disease, which interacted with HTT by regulating the expression of repressor element-1 silencing transcription (REST) (Packer et al., 2008). In addition, miR-22 has a potential protective effect on neurons, and it has been confirmed that miR-22 could delay the progression of HD by mediating neuronal synthesis and survival (Jovicic et al., 2013).
In this review article, we introduce the canonical miRNA biogenesis pathway and miRNA function and describe the most relevant brain-specific miRNAs associated with HD. Potential biomarkers involved in HD diagnosis and the use of miRNA-based therapeutic strategies are also highlighted.