Sex is a significant variable in the prevalence and incidence of neurological disorders. Sex differences exist in neurodegenerative disorders (NDs), where sex dimorphisms play important roles in the development and progression of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis.
- neurodegenerative diseases
- biomarkers
- microRNAs
- sex differences
- Alzheimer’s disease
- Parkinson’s disease
1. Introduction
Neurodegenerative diseases (NDs) have a huge impact on healthcare systems. They often are multifactorial with a complex pathophysiology, which makes an early diagnosis and identify effected treatments difficult. Several studies suggest that neuronal abnormalities start to appear 10–20 years before the onset of symptoms. Treatments are only symptomatic, and no pharmacological therapies are currently available to stop the underlying disease process [1]. There is a growing need for new tools having the ability to detect patients in their preclinical stage, monitor the disease progression, improve the understanding of various drug mechanisms targeting different pathogenic processes, and identify any response to treatment in a more sensitive and objective way. Using biomarkers, we can detect biochemical changes that appear when neurons begin to die. MicroRNAs (miRNAs) are highly conserved small noncoding RNAs regulating post-transcriptional gene expression. Since their discovery, a large number of miRNAs have been described. They are remarkably stable in human biofluids and easy to manage. As a result, miRNAs have emerged as powerful diagnostic or prognostic biomarkers in the pathophysiology of different neurodegenerative disorders and conditions affecting the central nervous system, in particular in older adults [2,3].
Gender differences have been a focus of interest in a growing number of studies in recent years. Several human conditions show gender or sex differences when considering their pathogenetic mechanisms, their progression, the age of onset, and treatment response. Recent studies suggest that the cause may lay in miRNA expression levels and that these differences might be influenced by a hormonal and genetic background [4]. Ignoring these differences could alter the meaning of the obtained results, as clusters or families of genes or molecular determinants, which have the potential to cause different disease onsets, could be missed or their functions and roles may not be further investigated. Moreover, failing to consider possible differences between males and females in miRNAs and in biomarkers in general could introduce a gender bias in the study.
2. microRNAs as Possible Biomarkers in Neurodegenerative Diseases
Biomarkers are powerful tools in biomedical research, and can be useful as supports in selecting the best therapeutic strategies. Testing-specific biomarkers allow monitoring modulations in normal or pathological conditions and give the opportunity to identify diseases in their early stages or to follow them throughout their progression. Clinical symptoms in the early stages might be very subtle, manifesting only when molecular and cellular alterations have already occurred. Thus, there is an increasing effort to develop molecular diagnostic and prognostic markers that meet certain requirements, such as easy accessibility, high specificity and sensitivity, low costs, and applicability to laboratories with standard equipment, for example peripheral biomarkers.
The most well established markers for the detection and monitoring of the preclinical and clinical stages of Alzheimer’s disease (AD) include cerebrospinal fluid (CSF) measures of Aβ42, total tau (t-tau), and phospho-tau (p-tau) [5], while the most promising for the diagnosis and monitoring of the progression of Parkinson’s disease (PD) is probably the assay of alpha-synuclein [6]. Other tools useful to support AD diagnosis are magnetic resonance imaging for hippocampal atrophy [7], the 18F-FDG PET to identify abnormal brain metabolism [8], and amyloid PET to detect the amyloid deposition [9]. However, these tests are invasive and expensive, and thus difficult to adopt in routine clinical practice.
An important novelty in this field is represented by peripheral circulating miRNAs. They are found in peripheral biofluids (saliva, blood, plasma, serum, urine), and therefore are easy to obtain from patients without any substantial risk to health. Moreover, miRNAs are remarkably stable in human biofluids and are easy to manage, thus they are increasingly emerging as promising powerful diagnostic or prognostic biomarkers of different pathophysiological processes [10] in conditions affecting the central nervous system, particularly in older adults. Interestingly, circulating miRNAs and miRNA profiles specific for AD, mild cognitive impairment (MCI) syndrome, PD, and amyotrophic lateral sclerosis (ALS) have been defined and characterized [11,12,13].
MicroRNAs are short non-coding RNAs (20–25 nucleotides), which are emerging as fundamental factors that are mostly displaying their functions at post-transcriptional levels. These short RNA sequences exert their action by binding to the 3’UTR of their target genes to negatively modulate their expression. Depending on the precision of the sequence complementarity, miRNAs can induce translational repression or mRNA degradation.
Each gene transcript might be targeted by several miRNAs and each single miRNA can bind and regulate hundreds of direct targets. Due to their number and complexity, miRNA–mRNA interactions are far from being well demonstrated.
Canonically, miRNAs are encoded as individual or cluster transcripts, with the latter containing several different miRNAs. Many miRNAs are located in the intron region of host protein coding genes [14]. Typically, miRNAs are generated from longer primary miRNA transcripts (pri-miRNA and pre-miRNA), which undergoing two sequential cleavages and passing to the RNase III enzymes Drosha and Dicer, produce the mature and biologically active molecules, which form the silencing complex together with the argonaute (AGO) protein.
3. MicroRNAs in the Brain: From Function to Gender Differences
Besides their relevant physiological roles, the deregulation of miRNAs is involved in the onset and progression of several human pathological conditions, including neurodegenerative diseases. Significant sex differences have been associated with physiological and pathological miRNA functions. Differences in their expression levels can lead to a propensity to develop specific diseases, such as the higher risk of developing Alzheimer’s disease observed in females.
Males and females have considerable differences in their hormonal and genetic profiles [4], and these variables are known to impact on microRNAs. In particular, sex steroid hormones, such as estrogens, progesterone, and testosterone, are known to regulate the expression of several microRNAs [15,16,17,18].
In recent years, a growing number of studies have highlighted the impacts of sex-related microRNA expression on brain development [19], with sex hormones showing the ability to bind to nuclear hormone receptors in order to induce a direct or indirect alteration in gene expression [20]. Furthermore, during miRNA biogenesis, sex hormones could also have a huge impact on miRNAs regulation. In fact, estradiol has been proven to alter the expression of AGO, Drosha, and Dicer [21].
Surprisingly, despite genomic distribution analysis showing that the human X chromosome has a higher density of miRNAs compared to autosomes and the Y-chromosome [22,23], no literature data are currently available on sex-chromosome-related microRNAs implicated in NDs.
Due to the extreme complexity of the miRNA-based regulatory circuitries, further in depth analyses will be required in order to understand in a more definite way their physiological and pathological activity, and to confirm their promising roles as biomarkers.
Focusing on the hot spot of this review, very high-throughput sequencing experiments were interpreted, suggesting that the number of miRNAs expressed in the human brain is over 1000, although currently only ~550 have been annotated in all humans [24]. Certain miRNAs and other non-coding RNAs have been suggested to act as “complexity multipliers” to help translate the ~25,000 human protein-coding genes into the human cerebral cortex, thus participating in neurodevelopmental and neurophysiological network integration [25]. The expression of brain miRNA changes continuously during brain development, with some miRNAs being enriched during the early phase of brain maturation and others during the late phase. Many miRNAs are highly expressed in the adult nervous system in a spatially and temporally controlled way in both normal physiology and in certain pathological conditions. Indeed, miRNAs have been implicated in various aspects of dendrite remodeling and synaptic plasticity, as well as in experience-dependent adaptive changes of neural circuits in postnatal developmental and the adult brain [26].
Moreover, some miRNAs are “exclusive” to different cell populations. As an example, in the human hippocampus, miR-124 and miR-320 are expressed mainly by neurons, in the substantia nigra miR-320 is mainly expressed by pigmented cells, while miR-107 is barely expressed by the same cell types [27]. The functions of brain miRNAs are clearly not related only to cell fate determination along developmental lineages, but also to neuroplasticity and to many other neurobiological functions, including the regulation of the synthesis of synaptic proteins, the morphogenesis of the dendritic spine, and in plasticity-related diseases [28].
Ziats and colleagues observed significant sex differences in the expression of 40 miRNAs in the prefrontal cortex of males and females. The majority of sex-biased gene expression occurred in adolescence (65%), suggesting that miRNA-targeted gene expression differences become most pronounced around puberty, probably due to the hormonal influence of this life stage [29]. Importantly, Murphy and colleagues observed a differential expression of microRNAs according to sex in the development of the cortex in rats [19]. They performed expression studies in male and female cortices isolated from postnatal day 0 (P0), postnatal day 7 (P7), and adult rats, showing differential miRNA levels between males and females at each developmental stage. They focused in particular on the miR-200 family, which has a “biphasic” expression, being higher in female rats at P0, inverting its expression at P7, and being higher in male rats during adult life. Moreover, Cui and colleagues identified 73 female-biased miRNAs and 163 male-biased miRNAs in several tissues, including brain tissue [30].
This entry is adapted from the peer-reviewed paper 10.3390/ijms22094423