ABSTRACT:
Neurological diseases, though having significant impact on individuals, thoroughly lack in knowledge and insight of epidemiology due to their complex nature. As of current research, neurological diseases are classified as the gradual functional deterioration and loss of neurons. Various neurological diseases have been recognised to have mutual aspects such as pathological nature, nervous mechanisms but also inflammatory responses in the nervous system. MicroRNAs (MiRNAs) are small non-coding RNAs that regulate the expression of most of the genes in humans. MiRNAs have been discovered to hold significant roles, many known and yet to find, in the pathogenesis of many diseases and conditions. This review depicts the potential for MicroRNAs, more specifically, MiRNA-146a as a potential target and biomarker for the treatment of neurological diseases, focusing on its involvement within Alzheimer’s disease (AD) in particular.
INTRODUCTION:
Initially identified in 1993 under the lab of Victor Ambrose, the discovery of MicroRNAs (MiRNAs) has paved the way for many possibilities and prospective insights to combating diseases and conditions; some having been looked into, and others completely unexplored [1]. MiRNAs are 21- to 23-oligonucleotide non-coding RNAs processed from longer transcripts, which regulate gene expression in most human genes. Conserved in many species alike, MiRNAs have widespread, conserved targets, and at some point, in development most genes have been regulated by these MiRNAs, providing a possibility of efficacy for treating diseases [2].
MiRNAs act through inhibition of protein expression of messenger RNA (mRNA) at post-transcription level within Argonaute proteins in order to regulate gene expression [3]. It is critical for many biological processes and animal development for MiRNAs to be expressed at a normal rate as dysregulated MiRNAs have been associated with multiple diseases [4]. A number of MiRNAs have been found to function for biologically diverse processes including that of cell death, neuronal patterning, immunity, and cell proliferation, just to state a few [5,6]. They can be secreted by living neurons and other cells within the CNS into extracellular vesicles (EVs) packaged in microvesicles, lipoprotein complexes and exosomes, thus carves the way for many neurological diseases to be linked to aberrant MiRNA expression and distribution [4, 7].
Amongst recent literature on potential targets for the treatment of diseases, MiRNAs are one of the most extensively characterized, yet heavily require more experimental confirmation [6]. As MiRNAs are a potential novel class of therapeutic targets, advances in research, particularly in its involvement within central nervous system (CNS) disease, would be beneficial, due to the CNS being the least accessible of all tissues [4].
A plethora of MiRNAs have been identified as having significant roles within processes in neurological diseases, and with the growing collection of literature on MicroRNAs, MiRNA-146a is often highlighted in its involvement with neurological diseases [8].
THE SIGNIFICANCE OF MICRORNA-146a:
MiRNA-146a is a small, non-coding, regulatory RNA that pertains to crucial roles in physiological and pathophysiological processes such as negatively regulating antiviral pathways, immune, and neuroinflammatory responses [5]. It is one of the most abundant MiRNAs that can be expressed in the CNS, and its polymorphisms are found to be closely associated to a majority of major neurological disorders not limited to but including: neuro autoimmune diseases, neurodegenerative diseases, neurological tumours, CNS trauma and cerebrovascular diseases [8]. These neurological diseases share nerve cellular mechanisms within pathogenesis, and are complicated processes from the limited knowledge that is currently available, thus cannot be treated or cured as of yet. MiRNA-146a is important in the development of these diseases as it has been shown, at post transcriptional level, to act via the inhibition of target genes such as: IRAK1, IRAK2, IRF-5, PTC1, RIG-I, STAT-1, TRAF6, and Numb [9, 10].
MiRNA-146a and its polymorphisms are not distributed by random; its particular sequences are carefully arranged to occupy very specific cellular microenvironments. Some of the miRNAs are expressed at higher levels in the exosomes than in the cells [7]. Two of the most important single-nucleotide polymorphisms (SNPs) in MiR-146a: rs2910164, and rs57095329, have been shown to influence the level of mature MiR-146a and are associated with the onset of several major neurological diseases, such as Alzheimer’s disease (AD), ischemic stroke (IS), epilepsy, and multiple sclerosis (MS) [8]. In animal models, it has been demonstrated that it is possible to improve and, in some cases, reverse neurological diseases and even tumours present on the brain and the central nervous system by restoring a normal level of MiRNAs and its polymorphisms [5]. For example, Giraldez et al. Discovered that zebrafish without MiRNA had problems with development of the brain, Chen et al. found that MiRNA-146a can protect the brain against cognitive decline in mice, Liu et al. Showed that treatment by restoring MiRNA-146a levels improves neurological and nerve function [11-13].
Polymorphisms of MiRNA-146a have possible clinical relevance and implication in pharmacogenetics [9]. As it is an upcoming, potential therapeutic target, its genetic polymorphisms would be critical in diagnosis and interindividual variation in drug response, as detecting underlying molecular responses and genetic environment can be detected earlier on, thus can prevent the onset of neurological diseases [14]. This epigenetic regulation of MiRNA-146 could justify why different patients respond differently to the same treatments, and as the brain and central nervous system are all so delicate and sensitive, further understanding how this gene works could be the answer to tailoring therapeutics and targets for treating neurological diseases [15].
INVOLVEMENT IN ALZHEIMER’S DISEASE:
Originally described by Alois Alzheimer in 1906 as “a peculiar severe disease process of the cerebral cortex”, Alzheimer’s disease (AD) is currently the most common cause of dementia in the elderly [16-18]. This neurodegenerative disorder is clinically defined as a progressive cognitive impairment including impaired cognition and judgement and in severe cases, psycho behavioural disturbances such as psychosis [19]. Disorders like AD are considered multifactorial, as they are currently recognised to emerge due to genetic programming and environmental influences but primary causes are still unknown. Neurodegeneration in AD most often goes unknown until severe and is estimated to start 20-30 years before clinical diagnosis, and the time from diagnosis to death is typically ~8 years [19,20]. This underlines why it would be crucial to find prospective targets and genes that could be used for early diagnosis or the treatment for AD.
AD is characterised by neuronal loss, the accumulation of senile plaques composed of β-amyloid proteins, neurofibrillary tangles (NFTs) and the activation of microglia and glia [21, 22]. These damaged and lost neurons, senile plaques and NFTs can ultimately pave way for the appearance of activated microglia [21]. These microglia, both in animal models and human brains, generate β-Amyloid, a pro-inflammatory agent, providing stimuli for neuroinflammation, inducing the activation of glia and many inflammatory components [22]. Though this just represents the very ‘tip of the iceberg’ of how AD can affect the brain, an understanding of this disease is critical in coming up with prevention and ways to combat AD before the damage to the nervous system becomes irreversible [23].
Inflammation clearly plays a critical role in the pathology of Alzheimer’s and is therefore recognised as a potential aspect to target, when it comes to treating AD. As stated before, microglia are the major producers of inflammatory factors, clustering in the brain during the early stage of pathogenesis of AD [24]. Inflammation in the CNS can in some circumstances be beneficial however, most often it can worsen pathology and cause secondary damage [22, 25]. In a healthy adult CNS, microglia are dormant but remain a vigilant state, and only respond to infection or CNS damage in order to restore CNS homeostasis [25].
Wenk and colleagues have studied the effects of nitric oxide flurbiprofen in reducing inflammation in the brain in rats, and although not a MiRNA, the study suggests that anti-inflammatory therapies may be effective in slowing onset of AD, which is where MiRNA-146a steps in [21].
MiRNA-146a is known to be an anti-inflammatory regulator that uses a negative feedback response. In conditions that are attended by cellular stress, such as Alzheimer’s, it is expected that MiRNAs have altered expression patterns and this is the case for MiRNA-146a [26]. It is known that MiRNA-146a is heavily upregulated in the brain of AD patients and in mice [27, 28]. In AD, MiRNA-146a levels are found to increase with disease severity and be local to brain regions most affected by neuroinflammation [29]. This is probably due to the anti-inflammatory nature of MiRNA-146a trying to decrease the inflammatory response from being too harsh and initiating more damage than good to the brain.
Cui et al. found MiRNA-146a to be increased to an average of 2.6-fold over age-matched controls in the temporal lobe of AD brains, and with increased expression correlating to increased senile plaque density, it may be assumed that this upregulation of MiRNA-146a may contribute to the progression of Alzheimer’s [30-32]. In a study by Shaik et al. this increase in MiRNA-146a can be partially eliminated by inhibiting the gene through NFκB, a protein complex that is the cause of this upregulation of MiRNA-146a [33]. The significance of this study is that it shows that there’s potential to not completely eradicate the expression of MiRNA-146a, which would be crucial as this can further lead to neurodegeneration as shown in animal models [34]. This sparks prospects into the clinical utilisation of an inhibitor targeting MiRNA-146a to slow down the progression of AD. As shown in a study by Mai et al., targeting and restoring normal levels of MiRNA-146a can alleviate the pathological process and the neurodegeneration of AD, thus further proving it possible to use MiRNA as a target in treating Alzheimer’s [35].
The ideal diagnostic technique and treatment for AD would be non-invasive and that can tackle the condition before onset of severe symptoms. As of present day, there is also no cure for AD, only drugs that relieve some AD symptoms and the diagnosis techniques include cognitive testing, neuroimaging and biomarker detection, and others, most of which only detect AD at a moderate to severe progress [15, 36]. With the further exploration of MiRNA-146a, it may be possible to use as a target for the diagnosis and treatment of Alzheimer’s as it is most commonly reported to be found abundant in cerebrospinal fluid and has demonstrated the potential pharmacological value when overexpressed [36-39].
CONCLUSION:
The research, literature, and execution of using MicroRNAs in the pharmaceutical industry and medicine is rapidly growing, ongoing and relatively promising. Whilst the technological and biological discoveries are encouraging, there are still many risks and obstacles to overcome before scaling up the use of MiRNAs in the real world [6]. The CNS being one of the most delicate and difficult to reach aspects in the human body, in order to treat and prevent neurological disorders, it is crucial to have a reliable resource in order to achieve this. MiRNAs being a natural agent, may have prospects in being able to assist clinically to the treatment of these diseases like Alzheimer’s but much more study is required. The road for the use of MiRNAs might be a long and hard road for therapeutics but MiRNA-146a could potentially be an answer to unlocking many doors for medicine, more so neurology and research in this area.
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Youth Medical Journal 