Dynamic glycosylation remodeling in neurological disorders

Synapses are key structures involved in transmitting information in the nervous system, and their functions rely on the regulation of various lipids. Lipids play important roles in synapse formation, neurotransmitter release, and signal transmission, and dysregulation of lipid metabolism is closely associated with various neurodegenerative diseases. The complex roles of lipids in synaptic function and neurological diseases have recently garnered increasing attention, but their specific mechanisms remain to be fully understood. This review aims to explore how lipids regulate synaptic activity in the central nervous system, focusing on their roles in synapse formation, neurotransmitter release, and signal transmission. Additionally, it discusses the mechanisms by which glial cells modulate synaptic function through lipid regulation. This review shows that within the central nervous system, lipids are essential components of the cell membrane bilayer, playing critical roles in synaptic structure and function. They regulate presynaptic vesicular trafficking, postsynaptic signaling pathways, and glial-neuronal interactions. Cholesterol maintains membrane fluidity and promotes the formation of lipid rafts. Glycerophospholipids contribute to the structural integrity of synaptic membranes and are involved in the release of synaptic vesicles. Sphingolipids interact with synaptic receptors through various mechanisms to regulate their activity and are also involved in cellular processes such as inflammation and apoptosis. Fatty acids are vital for energy metabolism and the synthesis of signaling molecules. Abnormalities in lipid metabolism may lead to impairments in synaptic function, affecting information transmission between neurons and the overall health of the nervous system. Therapeutic strategies targeting lipid metabolism, particularly through cholesterol modulation, show promise for treating these conditions. In neurodegenerative diseases such as Alzheimer's disease, Parkinson disease, and amyotrophic lateral sclerosis, dysregulation of lipid metabolism is closely linked to synaptic dysfunction. Therefore, lipids are not only key molecules in neural regeneration and synaptic repair but may also contribute to neurodegenerative pathology when metabolic dysregulation occurs. Further research is needed to elucidate the specific mechanisms linking lipid metabolism to synaptic dysfunction and to develop targeted lipid therapies for neurological diseases.

Mammalian central nervous system (CNS) development involves genetically controlled, opposing processes, such as neuronal proliferation, migration, differentiation and death. The natural, developmental cell death is a ubiquitous phenomenon and is referred to as «programmed cell death» (PCD). Apoptosis, a type of PCD, is a central event in normal development of the CNS, playing an important role in the control of cell numbers and the establishment of neuronal circuitry. During embryogenesis, apoptosis takes place in proliferating cell populations and is involved in CNS morphogenesis. At later stages of development, apoptosis occurs in postmitotic neurons, because of the competition for limited supply of neurotrophic factors, that originally suppress the endogenous genetic death programme. Data concerning apoptotic cell death during normal CNS development of domestic mammals is lacking, therefore information about the developmental pattern of this phenomenon is restricted to rodents and rabbits. In these animals it has been suggested that apoptosis follows a mono- or biphasic time course and is completed duringan early, critical period of CNS development, that is characterized by morphological and functional neuronal maturation and synapse formation. Apart from its role in CNS development, apoptosis has also been implicated in neuronal loss accompanying neurodegenerative diseases and traumatic brain injuries in humans and animals. In the domestic canine brain, it has been shown that neurons die via apoptosis in Alzheimer's-like dementia, cerebellar abiotrophy, global and focal ischemia and virus-induced encephalopathies. In addition, cell death in ruminants with transmissible spongiform encephalopathy has been reported to be apoptotic in nature. A plethora of studies using animal models have been employed to elucidate the mechanisms than govern cell loss in neurological disorders. These studies provided strong evidence that experimental lesions of the connections between CNS areas and withdrawal of neurotrophic factors result in an increase of apoptosis, that is age-dependent. Specifically, developing neurons are more dependent on the integrity of their connections than mature ones. In addition, the response of neurons to apoptotic stimuli shows regional specificity. According to epidemiologic studies, CNS disorders are of major concern for animal and human public health, with a high socioeconomic impact. A major goal of neuroscientists is the development of therapeutic approaches for CNS repair. Contemporary strategies that are under trial include neurotrophic factor substitution and transplantation of stem cells. Investigation of the principles and mechanisms controlling cell loss in neurodegenerative diseases and traumatic brain injuries are universally considered of high priority and hopefully will lead to novel therapeutic approaches, with encouraging outcome. The present review summarises recent data on the molecular mechanisms and factors controlling neuronal apoptosis during development and in pathological conditions, describes popular animal models used in lesion studies and discusses therapeutic approaches aiming at preventing or restricting apoptotic cell death.

Neuronal synapses are the functional units of communication in the central nervous system. This review describes the molecular mechanisms regulating synaptic transmission, plasticity, and circuit refinement. At the presynaptic active zone, scaffolding proteins including bassoon, piccolo, RIMs, and munc13 organize vesicle priming and the localization of voltage-gated calcium channels. Neurotransmitter release is mediated by the SNARE complex, comprising syntaxin-1, SNAP25, and synaptobrevin, and triggered by the calcium sensor synaptotagmin-1. Following exocytosis, synaptic vesicles are recovered through clathrin-mediated, ultrafast, bulk, or kiss-and-run endocytic pathways. Postsynaptically, the postsynaptic density (PSD) serves as a protein hub where scaffolds such as PSD-95, shank, homer, and gephyrin anchor excitatory (AMPA, NMDA) and inhibitory (GABA-A, Glycine) receptors are observed. Synaptic strength is modified during long-term potentiation (LTP) and depression (LTD) through signaling cascades involving kinases like CaMKII, PKA, and PKC, or phosphatases such as PP1 and calcineurin. These pathways regulate receptor trafficking, Arc-mediated endocytosis, and actin-dependent remodeling of dendritic spines. Additionally, synapse formation and elimination are guided by cell adhesion molecules, including neurexins and neuroligins, and by microglial pruning via the complement cascade (C1q, C3) and “don’t eat me” signals like CD47. Molecular diversity is further expanded by alternative splicing and post-translational modifications. A unified model of synaptic homeostasis is required to understand the basis of neuropsychiatric and neurological disorders.

The actin-based dynamics of dendritic spines play a key role in synaptic plasticity, which underlies learning and memory. Although it is becoming increasingly clear that modulation of actin is critical for spine dynamics, the upstream molecular signals that regulate the formation and plasticity of spines are poorly understood. In non-neuronal cells, integrins are critical modulators of the actin cytoskeleton, but their function in the nervous system is not well characterized. Here we show that alpha5 integrin regulates spine morphogenesis and synapse formation in hippocampal neurons. Knockdown of alpha5 integrin expression using small interfering RNA decreased the number of dendritic protrusions, spines, and synapses. Expression of constitutively active or dominant negative alpha5 integrin also resulted in alterations in the number of dendritic protrusions, spines, and synapses. alpha5 integrin signaling regulates spine morphogenesis and synapse formation by a mechanism that is dependent on Src kinase, Rac, and the signaling adaptor GIT1. Alterations in the activity or localization of these molecules result in a significant decrease in the number of spines and synapses. Thus, our results point to a critical role for integrin signaling in regulating the formation of dendritic spines and synapses in hippocampal neurons.

The central nervous system (CNS) is an immune-privileged organ because a selective permeability to exchange blood cells and substances from the circulatory system. Nevertheless, increasing evidence indicates that an extensive bi-directional communication takes place between the CNS and the immune system. Thus, the psyconeuroimmunology has emerged as a relative novel discipline to study interactions among psychological processes, brain functioning and the immune system. This especial issue of the Current Immunology Reviews contains nine comprehensive articles addressing the interactions between the immune and nervous systems in either physiological or pathological conditions. In an excellent review, Cordiglieri and Farina explain the role of astrocytes in initiating and tuning cerebral immune responses. Authors state that astrocytes promote or confine inflammatory processes and, in consequence, play a role in neuroprotection and CNS repair. Astrocytes act as immune-competent cells by secreting cytokines and chemokines, and participating in innate immunity. As reviewed by Tian and Rauvala, the communication between immune system and CNS is bi-directional, in fact, neurons participate in immune responses by controlling responses of microglia and T lymphocytes. Interestingly, the immune system also controls proliferation, differentiation, migration and self-renewal of adult neural stem cells, which reside in the wall of lateral ventricles of brain. Modulation of neural stem cells are mainly mediated by IL-6, IL-18, TNF-α, CNTF, LIF and IFN-γ [1–3]. Neuroinflammation plays a role in the etiology and/or progression of several neurological disorders. As reviewed by Ramos and Duran, rheumatoid arthritis is a systemic inflammatory disorder that affects the central and peripheral nervous system. As in other rheumatic diseases, TNF-α is one of the main mediators of CNS damage. Orozco et al. reviewed the effects of inflammatory reactions on neuronal excitability, cell survival impairment, and permeability to blood-borne molecules and cells. These pathological events and high levels of IL-1, IL-2, and TNF-α have been associated with epilepsy development and seizures. Cytokines and chemokines also modulate cognitive and emotional processes in the absence of overt immunological, physiological, or psychological challenges. Psychological stress and glucocorticoid-related immunosuppression is reviewed by Jauregui et al. They explain that stress increases the levels of glucocorticoids, which target resident microglia and decrease the ability of these brain cells to proliferate, to produce pro-inflammatory cytokines, and to produce toxic radicals. Brain Leonard summarizes evidence indicating that IL-1, IL-4, IL-6, IL-10, IL-13, IFN-α and TNF-α can affect cognitive and emotional processes as observed in major depression [4, 5]. Pro-inflammatory cytokines affect neuronal signaling by enhancing the glutamatergic system, which stimulates the tryptophan-kynurenine pathway. In an excellent review, Muller and Schwarz explain that high levels of IL-8 during pregnancy are associated with an increased risk for schizophrenia in the offspring. In this landmark review, the authors indicate that infections of the CNS in early childhood increase risk for developing psychoses and that IL-6 serum levels are elevated in patients with an unfavourable course of mental disease. This issue concludes with the striking proposal of Momin et al. who addressed the oncogenic and tumor-supporting potential of mesenchimal stem cells (MSCs) within the context of cancer treatment. This review states the risk for malignant transformation of MSCs, the in vivo interactions with tumor stroma and the immunosuppressive qualities of MSCs that facilitate evasion of the immune system by tumors. In summary, increasing evidence indicates that cytokines and chemokines modulate cerebral functions through multiple signaling pathways. All these interactions affect neural remodeling, synaptic plasticity, neurotransmitter releasing, neuronal regeneration, brain aging, cognitive and emotional processes, and mental disease progression. All these events modulate cognitive and emotional processes, and brain disease predisposition/progression.

Post-transcriptional regulation of gene expression is required for multiple aspects of neuronal development and function in the central nervous system. A sub-class of small non-coding RNA, called microRNAs (miRNAs), is emerging as key modulators of post-transcriptional gene regulation in numerous tissues, including the nervous system. Recent evidence has revealed a widespread role for miRNAs in various aspects of neuronal morphogenesis, including axogenesis, dendritogenesis, and synapse formation. Furthermore, dysregulation or altered expression of miRNAs has been associated with the pathogenesis of neurodevelopmental and psychiatric disorders. Here, we highlight recent advances in the study of miRNA-based regulation of neuronal development and their implications in neurological disorders.

Neuregulin-1 Enhances Depolarization-Induced GABA Release

Robust In Vivo Transduction of Nervous System and Neural Stem Cells by Early Gestational Intra Amniotic Gene Transfer Using Lentiviral Vector

Objective:This review aimed to summarize research progress regarding congenital cytomegalovirus (cCMV) infection-related nervous system diseases and their mechanisms.Data sources:All literature quoted in this review was retrieved from PubMed and Web of Science using the keywords “Cytomegalovirus” and “Neurologic disease” in English. To identify more important information, we did not set time limits.Study selection:Relevant articles were selected by carefully reading the titles and abstracts. Then, different diagnosis and clinical treatment methods for human CMV infection-related neurologic diseases were compared, and the main mechanism and pathogenesis of neurologic damage caused by CMV were summarized from the selected published articles.Results:cCMV infection is a major cause of neonatal malformation. cCMV can infect the fetal encephalon during early gestation and compromise neurodevelopment, resulting in varying degrees of neurologic damage, mainly including hearing impairment, central nervous system (CNS) infection, neurodevelopmental disorders, ophthalmic complications, cerebral neoplasms, infantile autism, epilepsy, and other neurologic abnormalities.Conclusions:cCMV infection-induced neurodevelopmental abnormalities, which were directly caused by fetal encephalon infection, thus inducing neuroimmune responses to damage nerve cells. Such abnormalities were also caused by suppression of the proliferation and differentiation of neural progenitor cells by CMV's gene products. cCMV infection in the fetal encephalon can also inhibit neuronal migration and synapse formation and indirectly trigger placental inflammation and thus disrupt the oxygen supply to the fetus.

Neurological disorders are a group of disorders with motor, sensory or cognitive damage, caused by dysfunction of the central or peripheral nervous system. Cyclin-dependent kinases 5 (Cdk5) is of vital significance for the development of the nervous system, including the migration and differentiation of neurons, the formation of synapses, and axon regeneration. However, when the nervous system is subject to pathological stimulation, aberrant activation of Cdk5 will induce abnormal phosphorylation of a variety of substrates, resulting in a cascade signaling pathway, and thus lead to pathological changes. Cdk5 is intimately related to the pathological mechanism of a variety of neurological disorders, such as A-β protein formation in Alzheimer’s disease, mitochondrial fragmentation in cerebral ischemia, and apoptosis of dopaminergic neurons in Parkinson’s disease. It is worth noting that Cdk5 inhibitors have been reported to have neuroprotective effects by inhibiting related pathological processes. Therefore, in this review, we will briefly introduce the physiological and pathological mechanisms of Cdk5 in the nervous system, focusing on the recent advances of Cdk5 in neurological disorders and the prospect of targeted Cdk5 for the treatment of neurological disorders.

Enigmatic Neural Pathways: Potentiating Viral Neuroinvasion Into the CNS.

Determinants of Axon Growth, Plasticity, and Regeneration in the Context of Spinal Cord Injury

The development of a single-cell zygote into an adult organism depends on highly coordinated, complex processes that control how and when cells divide, move, and change shape. The regulation of cell shape and motility is critical for the formation of functionally distinct tissues and organs and underlies a seminal event during the early development of multicellular organisms called gastrulation—when cells of different tissue types undergo large-scale rearrangements in relation to one another [1]. These processes also play an important role in the adult organism, for example, in wound healing, when fibroblasts and other cells migrate to the site of the injury to begin the process of healing [2], and in pathological situations. For instance, cancer cells migrate from their tissue of origin to populate distinct regions and organs in a process called metastasis [3], which often leads to organ failure and death in cancer patients. Cells move and change shape at the direction of signals from surrounding tissues, though the molecular mechanisms that drive these signals remain obscure. A new study reported in this issue of PLOS Biology sheds light on these processes by describing a novel molecular mechanism that links extracellular signals to cell shape changes in the nervous system [4]. The developing nervous system is a useful model for investigating such mechanisms, because a wide variety of extracellular cues direct neurons as they form the structures and functional connections that make up the central nervous system [5]–[7]. Nascent neurons often migrate from their origin in the lumen of the neural tube to populate distinct distal layers of their target tissues, resulting in the layering of neurons in the spinal cord and cerebral and cerebellar cortices. Neurons must also extend axons to specific regions of the nervous system or periphery to make synapses with the correct partners (e.g., muscles or other neurons), and they remain capable of remodeling throughout adulthood. For example, in the brain, synaptic contacts are dynamically formed, lost, and modified in size and strength in response to neuronal activity, a process referred to as synaptic plasticity [8]. These physical changes in neuronal and synaptic shape are thought to be a basis of learning and memory. Each of these cell motility events—gastrulation, neuronal migration, axon outgrowth, wound healing, and metastasis—share common cellular features. When observed in the process of development and migration, cells exhibit dynamic extension and retraction of plasma membrane protrusions called lamellipodia and filopodia that are fundamental to cell shape and motility events (Figure 1A) [9],[10]. Lamellipodia (from Latin, “thin plate protrusions”) extend dynamically from the leading edge of migrating cells and axonal growth cones, the specialized structures at the distal tips of developing axons that explore the environment and drive axon extension (Figure 1A). Filopodia (from Latin, “thread protrusions”) also emanate from the leading edges of migrating cells and growth cones, often from the edges of lamellipodia (Figure 1A). Dynamic lamellipodial protrusions are thought to generate the force required for cell and growth cone migration, whereas filopodia are thought to mediate the ability of migrating cells and growth cones to navigate their environments and sense cues as to their direction of migration and destination. Furthermore, filopodia along the shaft of dendrites are thought to be the initiating step in the formation of a new neuronal synapse, a process important in synaptic plasticity, learning, and memory. In this issue of PLoS Biology, the Research Article by Menna et al. [4] describes a signaling pathway beginning with an extracellular cue and ending with an actin-binding protein that regulates axonal filopodia formation. Figure 1 The actin cytoskeleton in lamellipodia and filopodia.

Mechanisms underlying the neuronal-based symptoms of allergy

Progesterone: The sexual hormone progesterone is a member of the steroid hormone family, and is the most important representative of the gestagenes sub-group. It plays an elementary role in the female menstruation cycle and is essential for the establishment and the maintenance of a pregnancy, however gestagenes like progesterone are also abundant in males. In 1990, the existence of steroids was described in different cells of the central nervous system (CNS) (Baulieu and Robel, 1990). Up until this point, the effect of sexual hormones on neural cells was rather unknown, other than in the well known regulatory centers of the hypothalamus. Since then the essential enzymes of steroid synthesis, cytochrome P450 side chain cleavage enzyme (P450scc) and 3 β-hydroxysteroid-dehydrogenase (3 β-HSD), have been detected in the central (Mellon et al., 1993) as well as in the peripheral nervous system (Schaeffer et al., 2010). Within the cerebellum Purkinje cells were identified as major sites for neurosteroid formation in the mammalian brain, synthesizing progesterone as well as estradiol (Tsutsui et al., 2011). Traditionally, the effects of progesterone are mediated by genomic mechanisms of classical progesterone receptors which act as transcription factors. Basically, two relevant isoforms, the N-terminal shortened A-form (PR-A, 86 kDa) and the native B-form (PR-B, 110 kDa) are known. Nevertheless, in addition to the genomic signaling pathway, other, non-genomic pathways have been described. The most important member of this non-genomic receptor family seems to be the "progesterone receptor membrane component 1" (PGRMC1). Neural expression of PR-A, PR-B and PGRMC1 could already be proven in different components of the CNS and the peripheral nervous system (PNS) e.g., the hypothalamus, the cerebellum and the dorsal root ganglia (Wessel et al., 2014b). Clinical relevance of progesterone: The effects of neurosteroids like progesterone on neuronal tissue in the CNS and PNS are of enormous therapeutic interest. The clinical relevance of progesterone has already been proven in many studies in different neural glial cells (De Nicola et al., 2013). Indeed, numerous preclinical studies verified the neuroprotective effects of progesterone after cranial traumatic brain and cerebral injuries. Furthermore, experimental data from various animal models emphasize the benefit of progesterone treatment on other neurological disorders like traumatic brain injury, peripheral nerve injury, amyotrophic lateral sclerosis and cerebral ischemia (Wessel et al., 2014b). Progesterone seems to have neuroprotective and anti-inflammatory influences on neuronal cells. For instance, post ischemic treatment with progesterone leads to a reduction of the necrotic area. Based on the versatile application of progesterone, and the outlined positive effects on poor prognosis neurological disorders of the CNS and PNS, the neurosteroids seem to be a very potent group for new therapeutic strategies. But the question is still whether progesterone serves as a universal stimulus for neuronal cells, or if there are therapeutical limitations to a progesterone treatment approach. Is it possible to treat children as well as adults with progesterone after injuries of the CNS or PNS? As there is no answer to this question yet, further basic research is mandatory. Recent studies reviewed the impact of progesterone on neonatal, juvenile and matured cells in the CNS and PNS. In the cerebellum, specifically in rat Purkinje cells, the expression of progesterone with high endogenous concentrations during the neonatal and juvenile periods have been shown (Wessel et al., 2014a). Here, progesterone induces denrito-, spino-, and somatogenesis (Tsutsui et al., 2011; Wessel et al., 2014a). In this study, an age-dependent increase in intracellular progesterone concentrations during the maturation of Purkinje cells and other neurons of the cerebellar cortex, along with an increased receptor expression in juvenile cells suggest that progesterone plays an important role during the physiological development of the cerebellar cortex (Figure 1a). Although Wessel et al. (2014a) demonstrated the expression of the classical progesterone receptors at all developmental stages in rats, the stimulation of matured cells with progesterone had no positive effects concerning neuroplasticity (Figure 1b). Interestingly, at the same time points, the positive impact of progesterone could be verified in the PNS. In primary cultures from chicken dorsal root ganglia (DRG) treated with progesterone, a significant enhancement of neuritic outgrowth was evident (Figure 1a). Blocking of progesterone receptors with mifepristone leads to the extinction of this effect (Olbrich et al., 2013). These results give a strong hint that the use of neurosteroids can be a strategy in pediatric neonatology and traumatology, but at this time point it seems to be limited to juvenile stages and is not applicable in adults. Therefore, we have to investigate and to understand the expression and regulation of the different progesterone receptors in the nervous system, especially in adults. Beside these data progesterone often acts in concert with estrogen. In Purkinje cells, estrogen also promotes dendritic growth, spino- and synaptogenesis during neonatal life (Tsutsui et al., 2011).Figure 1: Impact of progesterone on neuronal cellsa) Progesterone stimulated juvenile neuronal cells in the central nervous system show an increase in dendritogenesis, somatogenesis and spinogenesis. Additionally, cells in the peripheral nervous system show an enlargement in the growth cone after progesterone incubation.b) Adult neurons show no effects after progesterone treatment, neither in the central nervous system nor in the peripheral nervous system. We assume that miRNAs inhibit or degrade the mRNA of progesterone receptors, so that the cell loses its sensitivity to progesterone.c) The regulation of these miRNAs by local or systematic inhibition might increase the number of functional progesterone receptor mRNA molecules. This may result in an increased sensitivity to progesterone in adult stages, possibly leading to effects comparable to those seen in juvenile neuronal cells.MicroRNAs and their relevance in neurology and neurodegenerative diseases: Many studies have been carried out to analyze the function, and subsequently confirm the relevance of microRNAs (miRNA) in the CNS. It has been shown that the biogenesis of miRNAs is crucial for the development and the functionality of neuronal structures. In different independent studies of the cerebral cortex and the cerebellum of mice, it became apparent that inhibition or a complete loss of Dicer leads to different manifestations of neurodegeneration (Hong et al., 2013). MiRNAs are short (21–23 nucleotide, nt), highly conserved, non-coding RNAs. They play a crucial role in posttranscriptional gene regulation e.g., neuroplasticity-related processes (Hommers et al., 2015). The biogenesis of miRNAs, a multistage process, is an important procedure to ensure their functional efficiency. In the first step, the primary transcript of miRNAs (pri-miRNA) is generated in the nucleus. Pri-miRNA has a length of 500–3,000 nucleotides and carries a poly-A-tail at its 3′-end, as well as a 7-methylguanosine cap. Subsequently, the primary transcript is converted into a hairpin structure and cleaved into an approximately 70 nt precursor form (pre-miRNA) by RNase III (Drosha). Pre-miRNA is then transported from the nucleus into the cytoplasm by two proteins, Exportin 5 and Ras-related nuclear protein. In the cytoplasm the RNaseIII, Dicer, and its co-factor Tar RNA-binding protein (TRBP) process the pre-miRNA by cleaving the loop structure and the pre-miRNA into 21–23 nt miRNAs. The single, mature miRNA strands are loaded onto the Argonaute homologue protein (Ago2) in order to form the RNA-induced silencing complex (RISC). In this conformation the miRNA binds to its target mRNA. MiRNAs bind to the 3′ untranslated regions (3′UTR) of their target mRNA and can affect it in two different ways depending on the complementarity to its binding sequence. The transcription can either be inhibited or the mRNA can be degraded completely. A partial complementarity leads to inhibition whereas a perfect base matching causes degradation of the mRNA. Hong et al. (2013) showed that disruption of miRNA biogenesis results in microcephaly in differentiated neurons of the cerebral cortex in Dicer-knockout mice. In comparison to control mice without disruption in pre-miRNA procession, brains of knockout mice were significantly smaller. Total loss of miRNA function leads to a reduced cell soma size of mature neurons and a reduced neurite growth. In a second study it became clear that a knockout of the Dicer enzyme in Purkinje cells is accompanied by dramatic consequences. In contrast to the results of Hong et al., the Dicer-knockout led to cellular death and cerebellar degeneration, and at least induced ataxia (Schaefer et al., 2007). Disruptions due to a knockout of the Dicer enzyme show explicit similarities to different mouse models of neurodegenerative diseases. Apart from the universal step of correct processing of the miRNA, several miRNAs are known to disturb the neuronal development, like the loss of miR-592. Also the involvement of miRNAs in neurodegenerative disease development should not be underestimated. Therefore the emphasis in the investigation of neurodegenerative disorders over the last decade has been concentrated on the involvement of miRNAs. Several miRNAs show a negative effect in the pathogenesis of Parkinson's disease, Alzheimer's disease, Huntington's disease, epilepticus and multiple-system atrophy. For instance in multiple-system atrophy, one single miRNA called miR-202 is the key factor. Effect of miRNAs on progesterone and its receptors: The existence of numerous mRNA targets implicate that miRNAs are capable to regulate thousands of genes. This is why miRNAs are essential in various development stages, tissues and diseases. In terms of progesterone, several studies revealed the effect of miRNAs on progesterone and its receptors. Most of these studies deal with the investigation of miRNAs in breast tumors and their significance in the establishment and maintenance of pregnancy. In both cases the amount of progesterone and its receptors are regulated by different miRNAs. MiR-200a is one key mediator in the decline of progesterone receptor function leading to term and preterm labor (Williams et al., 2012). Progesterone metabolism is up-regulated and the sensitivity of the receptors for progesterone is down-regulated. Apart from these data, progesterone and its receptors could have a strong impact in the nervous system. We know that the classical progesterone receptors are most abundant and sensitive in the early stages of neuronal development. Clinical research in brain injuries, animal models, or even traumata in childhood show promising results when treated with progesterone. The present challenge is to understand the post-transcriptional mechanisms in neuronal cells and to expand the positive effects of progesterone in adulthood. miRNAs, the most important post-transcriptional regulators, are implicated in brain development and in the formation of neurological disorders. Complete comprehension of miRNA function in the neuroscientific field could help to reveal the versatile molecular consequences of miRNA interaction. The understanding of these mechanisms is supposed to be the key to designing new therapeutic tools for the treatment of neuronal damage, in which miRNAs could be used as target molecules for drugs. One promising approach could be the possibility to regulate specific miRNAs by the systematic or local use of miRNA inhibitors, known as antagomirs, and stimulators, known as mimics which are artificial RNA molecules (Figure 1c). An investigation into the gene encoding progesterone resulted in the detection of several binding sites for miRNAs at the 3' UTR which appear to regulate its expression. This opens up new possibilities to interfere with the functionality of the miRNAs that target these sites. One example for a promising miRNA mimic is miR-193b-mimic, a down-regulator of progesterone receptors in a breast cancer cell line (Younger and Corey 2011). This knowledge strongly encourages us to investigate progesterone receptor-regulating miRNAs. Founded on the state of knowledge about the interference of miRNAs in neuronal structures, the main goals are: (1) to reveal regulation mechanisms concerning the classical progesterone receptors, (2) to synthesize mimics and/or antagomirs to replicate the positive impact of progesterone in mature neuronal cells (Figure 1c). We would like to acknowledge D. Terheyden-Keighley for the critical reading of this article. We gratefully thank FoRUM (RUB) for financial support (F812-2014).