The Role of MicroRNA in the Pathogenesis and Diagnosis of Neurodegenerative Diseases

Review Article

Austin Alzheimers J Parkinsons Dis. 2014;1(3): 10.

The Role of MicroRNA in the Pathogenesis and Diagnosis of Neurodegenerative Diseases

Michal Prendecki and Jolanta Dorszewska*

Department of Neurology, Poznan University of Medical Sciences, Poland

*Corresponding author: Jolanta Dorszewska, Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, 49 Przybyszewskiego St, PL 60-355 Poznan, Poland.

Received: October 16, 2014; Accepted: November 09, 2014; Published: November 10, 2014


Today, Neurodegenerative Diseases (NDs) constitute one of the most significant issues in public healthcare. One of these NDs, Alzheimer's disease (AD), affects more than 24 million people worldwide. Scientists all over the world are searching for biomarkers that are vital for ND pathogenesis and diagnosis. It seems that one of these promising biomarkers might be microRNA (miRNA), whose biosynthesis is understood quite well.

Currently known human miRNAs (~2600) are involved in numerous physiological and pathological processes. Recent studies have sought specific miRNAs that are significant for the pathogenesis and diagnosis of NDs. Most miRNAs are common for many NDs, however, few seem to be specific to individual diseases: AD (e.g. let-7f, miR-125b, -193b), Parkinson's disease (e.g. miR-19b, -34b/c, -133b), and frontotemporal dementia (e.g. miR-132, -212).

It seems that finding specific miRNAs for individual NDs may contribute to early and certain diagnosis and to introducing effective therapy.

Keywords: miRNA; Neurodegeneration; Alzheimer's disease; AD; Parkinson's disease; PD


3'-UTR: 3'-Untranslated Region of mRNA; AD: Alzheimer's disease; APP: Amyloid Precursor Protein; ASN: α-synuclein; Aβ: Beta-Amyloid; BACE1: Beta-Site APP Cleaving Enzyme 1; CNS: Central Nervous System; DNs: Dopaminergic Neurons; FTD: Frontotemporal Dementia; LRRK2: Leucine-Rich Repeat Kinase 2; MCI: Mild Cognitive Impairment; miRISC: miRNA-Induced Silencing Complex; miRNA: microRNA; MMSE: Mini-Mental State Examination; ncRNA: Noncoding RNA; NDs: Neurodegenerative Diseases; nt: Nucleotides; PD: Parkinson's disease; pre-miRNA: Premature microRNA; pri-miRNA: Primary microRNA; ROS: Reactive Oxygen Species; RT-qPCR: Real Time Quantitative PCR


Neurodegenerative Diseases (NDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are a non-homogeneous group of various disorders affecting the Central Nervous System (CNS), mostly by excessive apoptosis of neurons in diverse locations of the human brain. Both the region and neuron types that are affected determine the nature of the cognitive, behavioral and motor deficits, which are fairly specific to each disease. Moreover, the significant heterogeneity of clinical symptoms of NDs makes a definitive diagnosis feasible only upon a postmortem histopathological examination of brain tissue.

NDs have become one of the most significant public health issues in recent years, since 24 million people are suffering from AD worldwide and the number of patients is expected to double in the next 15 years [1]. Yet current knowledge is still incomplete regarding the genetic basis underlying changes taking place on both a molecular and cellular level. As a consequence, there are no available therapies that would effectively modify the disease, and contemporary diagnostic tools are not able to detect early changes that take place for years prior to the actual symptoms, which manifest themselves when most of the brain damage has already been done [2].

Attempts to explain the pathogenesis of neurodegenerative diseases via genetic mutations were not entirely fruitful and researchers realized that there must be another level of neuronal homeostasis regulation [2]. Another piece of the puzzle was uncovered along with sequencing of the human genome, when it turned out that more than 95% of human cellular RNAs are noncoding RNAs (ncRNAs) [3]. These small molecules seem to be plentiful in the human brain and in other parts of the nervous system; later on it was shown that they control its proper function and development [4]. Although previously underappreciated, ncRNAs have proved to be pivotal in degenerative processes, hence neurodegeneration may be regarded as an "RNA disorder" where one class of ncRNAs, namely microRNAs (miRNAs), seems to play the leading role [2].

miRNAs are a conserved group of short (about 22 nucleotides (nt)), single-stranded RNA molecules [5] that play a significant role in "fine-tuning" gene expression by semi-complementary hybridizing to mRNA and suppressing its effective translation [6]. Since their discovery in 1993 by Lee et al. [7], miRNAs have become one of the mostly researched groups of small noncoding nucleic acids. There were over 35 thousand records on PubMed as of September 2014 (, and information on miRNAs is being gathered in specialized databases, e.g. at, whose most recent version (21st edition; June 2014) contains information on nearly 2600 sequences of mature human miRNAs.

To select relevant studies for this review, the authors conducted multiple searches through public databases, including PubMed, Scopus and Google Scholar, by using the following search strategy: ("Alzheimer's disease" or "AD", or "Parkinson's disease" or PD, or "Frontotemporal dementia" or "FTD") and ("microRNA" or "miRNA") and ("biomarker" or "SNP", or "genetic polymorphism" or "mutation"). The last search was performed in September of 2014. A subsequent search through review articles and references facilitated finding additional eligible studies.

Role of miRNA in physiological conditions

Biosynthesis of miRNA

The first step of miRNA biosynthesis is RNA polymerase IImediated transcription of primary miRNA (pri-miRNA) either from independent miRNA genes or the introns of protein-coding mRNAs [8]. Similarly to coding mRNAs, pri-miRNAs are polyadenylated and their expression is regulated by transcription factors [9].

pri-miRNAs tend to fold into secondary structures containing imperfectly base-paired stem loops which are subsequently cleaved into about 70-nucleotide hairpins of premature-miRNAs (premiRNAs) by the nuclear complex RNase III type endonuclease Drosha and the DGCR8 protein [8]. Alternative pathways have also been described, e.g. pre-miRNAs may bypass the Drosha/DGCR8 step and be synthesized from very short introns (mirtrons) as a result of debranching or splicing [8,10].

pre-miRNAs, after processing by the Drosha complex, are transferred through the nuclear membrane to the cytoplasm via a Ran-GTP-dependent mechanism by Exportin-5 [8]. Outside the nucleus, pre-miRNAs are cleaved close to the terminal loop by the second RNase III-type enzyme, a complex of Dicer and its cofactor TAR RNA-binding protein 2, thus giving RNA duplexes of roughly 22 nt [8]. The newly created short RNA duplexes bind to a glycinetryptophan repeat-containing protein of 182 kDa and an argonaute protein forming the miRNA-Induced Silencing Complex (miRISC) [11]. Next, one of the two strands, the so-called "passenger miRNA" (also known as "complementary star-form miRNA", "miRNA*" or "miRNA-3p"), is released, while the other strand, designated as the "guide strand", "mature miRNA", or "miRNA-5p", remains within miRISC [12,13]. Current studies have implied that both arms (3' and 5' for -3p and -5p, respectively [14]), of the pre-miRNA hairpin can give rise to mature miRNAs [15].

Full miRISCs recognize target mRNAs by hybridizing the seed region of miRNA (between the 2nd and 8th nt of the miRNA) to the complementary region in the 3' untranslated region of mRNAs (3'- UTR) [16-18]. Bounding miRISCs to mRNAs inflicts translational repression [11].

Current studies have highlighted that the down-regulation effects of miRNAs/miRISCs occur mostly through mRNA degradation rather than translational repression [19]. Moreover, recent data show that efficient repression requires the presence of typically > 100 copies of miRNA per cell [20]. Hence, poorly expressed miRNAs may play little or no part in adjusting gene expression [21]. Additionally, molecular sponges may bind free miRNA and prevent hybridization to mRNA targets [22,23].

Various functions of miRNA

miRNA research on the mammalian brain started in 2003, when Krichevsky et al. conducted microarray studies and showed significant changes in miRNA levels during brain development [24]. Next-generation sequencing as used by Landgraf et al. in 2007 constituted another leap which allowed identifying differences inmiRNA expression in various cell types and parts of the brain [25].

Today, miRNAs are believed to take part in both neuronal and brain development as well as in many physiological processes. The role of miRNA in developing neurons was proven by Yoo et al. in 2011. They discovered that miR-9* and miR-124 induce compositional changes of SWI/SNF-like BAF chromatin-remodeling complexes and control multiple genes regulating neuronal differentiation and function. They showed that expression of miR-9/9* and miR-124 in human fibroblasts induced (further augmented by Neurogenic differentiation factor 2) conversion into neurons. In their experiment the addition of ASCL1 and MYT1L transcription factors enhanced the speed of conversion and differentiation but was not alone-sufficient to trigger the conversion [26].

In physiological conditions, miRNAs act as expression controllers and are responsible for maintaining proper levels of various proteins in cells [27]. miRNA genes are not translated into proteins, instead they usually bind with the 6-nucleotide long semi-complementary seed sequence to the 3'-UTR and sporadically to the 5'-UTR or coding regions of target mRNAs [19], thus inducing gene silencing or, rarely, over-expression [23]. Bioinformatic analyses show that miRNAs may regulate the expression of over 60% of all human proteincoding genes [28,29]. MiRNAs are involved in countless biological processes, such as development, differentiation, and growth [6,15,30]. What has been shown lately is that a single miRNA molecule interacts with numerous mRNAs, and mRNA expression may be regulated by various miRNAs, thus starting a huge net of co-interactions [31-33]. miRNAs are mostly considered to "fine-tune" gene expression and to regulate development and tissue homeostasis [34].

It has been found that miRNAs are also involved in synaptic plasticity, as shown by Gao et al. They investigated SIRT1, sirtuin 1, a gene having systemic roles in cardiac function, DNA repair and genomic stability. Recent studies suggest that SIRT1 plays a role in normal brain physiology as well as in neurological disorders. Gao et al. also found that proper activity of SIRT1 increases, whereas its lossof- function impairs synaptic plasticity via a microRNA-mediated mechanism involving CREB and miR-134. They also showed that SIRT1 limits the expression of miR-134 via a repressor complex containing transcription factor YY1. Overexpression of miR-134 has been shown to lower the levels of CREB and the brain-derived neurotrophic factor, thus impairing synaptic plasticity, which is the key mechanism controlling memory [35].

Other examples of miRNA involved in the function and development of neurons and the CNS are: miR-9 - responsible for neuronal differentiation, formation of the cortex, neurogenesis and brain development; miR-124 - controlling serotonin synaptic facilitation, neuritis development, neuron differentiation; miR-125b - adjusting spine width, dendritic branching and weakening synaptic transmission; miR-132 - inducing neural outgrowth, regulating dendritic complexity, spine width, stimulating synaptic transmission; miR-137 - inhibiting spine development and maturation as well as inducing proliferation of neuronal progenitor cells; miR-138 - regulating the size of the spine; miR-375 - repressing the density of dendrites; and miR-379/410 cluster - inhibiting dendritic outgrowth [36]. Further miRNAs, such as let-7 and miR-9, have been described as stimulating differentiation, while miR-25 has been shown to induce the proliferation of neural stem cells [37].

Various miRNA-mediated mechanisms of neuronal damage in neurodegenerative diseases

miRNAs are probably associated with numerous pathological processes, such as response to oxidative stress, cell cycle disorders, neuroinflammation, clearance of pathological proteins and cholesterol trafficking. All of these contribute to the development of NDs (see Figure 1).

Citation: Prendecki M and Dorszewska J. The Role of MicroRNA in the Pathogenesis and Diagnosis of Neurodegenerative Diseases. Austin Alzheimers J Parkinsons Dis. 2014;1(3): 10. ISSN: 2377-357X