Functions of Noncoding RNAs in Neural Development and Neurological Diseases

The development of the central nervous system (CNS) relies on precisely orchestrated gene expression regulation. Dysregulation of both genetic and environmental factors can affect proper CNS development and results in neurological diseases. Recent studies have shown that similar to protein coding genes, noncoding RNA molecules have a significant impact on normal CNS development and on causes and progression of human neurological disorders. In this review, we have highlighted discoveries of functions of noncoding RNAs, in particular microRNAs and long noncoding RNAs, in neural development and neurological diseases. Emerging evidence has shown that microRNAs play an essential role in many aspects of neural development, such as proliferation of neural stem cells and progenitors, neuronal differentiation, maturation, and synaptogenesis. Misregulation of microRNAs is associated with some mental disorders and neurodegeneration diseases. In addition, long noncoding RNAs are found to play a role in neural development by regulating the expression of protein coding genes. Therefore, examining noncoding RNA-mediated gene regulations has revealed novel mechanisms of neural development and provided new insights into the etiology of human neurological diseases.     

Think locally: control of ubiquitin‐dependent protein degradation in neurons

The nervous system coordinates many aspects of body function such as learning, memory, behaviour and locomotion. Therefore, it must develop and maintain an intricate network of differentiated neuronal cells, which communicate efficiently with each other and with non‐neuronal target cells. Unlike most somatic cells, differentiated neurons are post‐mitotic and characterized by a highly polarized morphology that determines the flow of information. Among other post‐translational modifications, the ubiquitination of specific protein substrates was recently shown to have a crucial role in the regulation of neuronal development and differentiation. Here, we review recent findings that illustrate the mechanisms that mediate the temporal and spatial control of neuronal protein turnover by the ubiquitin–proteasome system (UPS), which is crucial for the development and function of the nervous system.     

Synapse formation and plasticity: recent insights from the perspective of the ubiquitin proteasome system

The formation of synaptic connections during the development of the nervous system requires the precise targeting of presynaptic and postsynaptic compartments. Furthermore, synapses are continually modified in the brain by experience. Recently, the ubiquitin proteasome system has emerged as a key regulator of synaptic development and function. The modification of proteins by ubiquitin, and in many cases their subsequent proteasomal degradation, has proven to be an important mechanism to control protein stability, activity and localization at synapses. Recent work has highlighted key questions of the UPS during the development and remodeling of synaptic connections in the nervous system.     

Wnt Signaling in the Vertebrate Central Nervous System: From Axon Guidance to Synaptic Function

Regulation of cell signaling by Wnt proteins is critical for the formation of neuronal circuits. Wnts modulate axon pathfinding, dendritic development, and synaptic assembly. Through different receptors, Wnts activate diverse signaling pathways that lead to local changes on the cytoskeleton or global cellular changes involving nuclear function. Recently, a link between neuronal activity, essential for the formation and refinement of neuronal connections, and Wnt signaling has been uncovered. Indeed, neuronal activity regulates the release of Wnt and the localization of their receptors. Wnts mediate synaptic structural changes induced by neuronal activity or experience. New emerging evidence suggests that dysfunction in Wnt signaling contributes to neurological disorders. In this article, the attention is focused on the function of Wnt signaling in the formation of neuronal circuits in the vertebrate central nervous system.The formation of neuronal connections requires the navigation of axons to their appropriate synaptic targets, the formation of terminal branches, and the assembly of functional synapses. These processes greatly depend on the proper dialogue between axons and their environment as they navigate to their target, and between axons and their postsynaptic dendrites during synapse assembly. A combination of secreted molecules and transmembrane proteins modulates these processes. Studies over the last 10 years have revealed an essential role for Wnt signaling in axon pathfinding, dendritic development, and synapse assembly in both central and peripheral nervous systems. Wnts also modulate basal synaptic transmission and the structural and functional plasticity of synapses in the central nervous system. Studies of Wnts in the nervous system have significantly contributed to our current understanding of the molecular mechanisms that control neuronal circuit assembly. These studies have also shed light into fundamental aspects of cell signaling such as novel mechanisms of protein secretion (Korkut et al. 2009) and receptor dynamics (Sahores et al. 2010). Here I review the mechanisms by which Wnts modulate axon guidance and synapse formation in the vertebrate central nervous system. I also discuss the increasing evidence in support for a role of Wnts in basal synaptic transmission, synaptic plasticity, and neurological disorders.     

HIPK2 in the physiology of nervous system and its implications in neurological disorders

HIPK2 is an evolutionary conserved serine/threonine kinase with multifunctional roles in stress response, embryonic development and pathological conditions, such as cancer and fibrosis. The heterogeneity of its interactors and targets makes HIPK2 activity strongly dependent on the cellular context, and allows it to modulate multiple signaling pathways, ultimately regulating cell fate and proliferation. HIPK2 is highly expressed in the central and peripheral nervous systems, and its genetic ablation causes neurological defects in mice. Moreover, HIPK2 is involved in processes, such as endoplasmic reticulum stress response and protein aggregate accumulation, and pathways, including TGF-β and BMP signaling, that are crucial in the pathogenesis of neurological disorders. Here, we review the data about the role of HIPK2 in neuronal development, survival, and homeostasis, highlighting the implications in the pathogenesis of neurological disorders, and pointing out HIPK2 potentiality as therapeutic target and diagnostic or prognostic marker.     

Intercellular protein-protein interactions at synapses

Chemical synapses are asymmetric intercellular junctions through which neurons send nerve impulses to communicate with other neurons or excitable cells. The appropriate formation of synapses, both spatially and temporally, is essential for brain function and depends on the intercellular protein-protein interactions of cell adhesion molecules (CAMs) at synaptic clefts. The CAM proteins link pre- and post-synaptic sites, and play essential roles in promoting synapse formation and maturation, maintaining synapse number and type, accumulating neurotransmitter receptors and ion channels, controlling neuronal differentiation, and even regulating synaptic plasticity directly. Alteration of the interactions of CAMs leads to structural and functional impairments, which results in many neurological disorders, such as autism, Alzheimer’s disease and schizophrenia. Therefore, it is crucial to understand the functions of CAMs during development and in the mature neural system, as well as in the pathogenesis of some neurological disorders. Here, we review the function of the major classes of CAMs, and how dysfunction of CAMs relates to several neurological disorders.     

The F-Box Protein MEC-15 (FBXW9) Promotes Synaptic Transmission in GABAergic Motor Neurons in C. elegans

Ubiquitination controls the activity of many proteins and has been implicated in almost every aspect of neuronal cell biology. Characterizing the precise function of ubiquitin ligases, the enzymes that catalyze ubiquitination of target proteins, is key to understanding distinct functions of ubiquitination. F-box proteins are the variable subunits of the large family of SCF ubiquitin ligases and are responsible for binding and recognizing specific ubiquitination targets. Here, we investigated the function of the F-box protein MEC-15 (FBXW9), one of a small number of F-box proteins evolutionarily conserved from C. elegans to mammals. mec-15 is widely expressed in the nervous system including GABAergic and cholinergic motor neurons. Electrophysiological and behavioral analyses indicate that GABAergic synaptic transmission is reduced in mec-15 mutants while cholinergic transmission appears normal. In the absence of MEC-15, the abundance of the synaptic vesicle protein SNB-1 (synaptobrevin) is reduced at synapses and increased in cell bodies of GABAergic motor neurons, suggesting that MEC-15 affects the trafficking of SNB-1 between cell bodies and synapses and may promote GABA release by regulating the abundance of SNB-1 at synapses.     

Current and Novel Aspects on the Non-lysosomal β-Glucosylceramidase GBA2

The non-lysosomal β-glucosylceramidase GBA2 (EC3.2.1.45, GH116) is ubiquitously expressed in various mammal tissues and cell types where it catalyzes the hydrolysis of glucosylceramide into glucose and ceramide. Although it has been known for many years that the central nervous system is the main site of GBA2 expression and activity, little information has been available so far on the role of this protein in the neuronal development, senescence and homeostasis. In the present review, we summarize the state-of-the art of this enzyme and in particular, we focus on the current knowledge on its structure, its physico-chemical properties and its subcellular localization. Data on the involvement of GBA2 in physiopathological processes are also described, with particular emphasis on the studies that have indicated the direct involvement of GBA2 in neuronal development and neurological disorders. A discussion of some open questions and future perspectives related to GBA2 are finally reported. We conclude that further investigations on this β-glucosylceramidase will provide new clues about the physiology of the central nervous system.     

The tripartite synapse: roles for gliotransmission in health and disease

In addition to being essential supporters of neuronal function, astrocytes are now recognized as active elements in the brain. Astrocytes sense and integrate synaptic activity and, depending on intracellular Ca(2+) levels, release gliotransmitters (e.g. glutamate, d-serine and ATP) that have feedback actions on neurons. Recent experimental results have raised the possibility that quantitative variations in gliotransmission might contribute to disorders of the nervous system. Here, we discuss targeted molecular genetic approaches that have demonstrated that alterations in protein expression in astrocytes can lead to serious changes in neuronal function. We also introduce the concept of 'astrocyte activation spectrum' in which enhanced and reduced gliotransmission might contribute to epilepsy and schizophrenia, respectively. The results of future experimental tests of the astrocyte activation spectrum, which relates gliotransmission to neurological and psychiatric disorders, might point to a new therapeutic target in the brain.     

Microglial Interferon Signaling and White Matter

Microglia, the resident immune cells of the CNS, are primary regulators of the neuroimmune response to injury. Type I interferons (IFNs), including the IFNαs and IFNβ, are key cytokines in the innate immune system. Their activity is implicated in the regulation of microglial function both during development and in response to neuroinflammation, ischemia, and neurodegeneration. Data from numerous studies in multiple sclerosis (MS) and stroke suggest that type I IFNs can modulate the microglial phenotype, influence the overall neuroimmune milieu, regulate phagocytosis, and affect blood–brain barrier integrity. All of these IFN-induced effects result in numerous downstream consequences on white matter pathology and microglial reactivity. Dysregulation of IFN signaling in mouse models with genetic deficiency in ubiquitin specific protease 18 (USP18) leads to a severe neurological phenotype and neuropathological changes that include white matter microgliosis and pro-inflammatory gene expression in dystrophic microglia. A class of genetic disorders in humans, referred to as pseudo-TORCH syndrome (PTS) for the clinical resemblance to infection-induced TORCH syndrome, also show dysregulation of IFN signaling, which leads to severe neurological developmental disease. In these disorders, the excessive activation of IFN signaling during CNS development results in a destructive interferonopathy with similar induction of microglial dysfunction as seen in USP18 deficient mice. Other recent studies implicate “microgliopathies” more broadly in neurological disorders including Alzheimer’s disease (AD) and MS, suggesting that microglia are a potential therapeutic target for disease prevention and/or treatment, with interferon signaling playing a key role in regulating the microglial phenotype.     

Synapses and growth cones on two sides of a highwire

The formation of the nervous system during embryonic development is controlled by a complex network of signaling pathways which ensure proper migration and targeting of neuronal projections. Likewise, the function of the adult nervous system relies on complex dynamic interactions between the presynaptic and postsynaptic terminals. Here, we review recent advances in understanding the molecular pathways underlying these seemingly distinct processes. These studies reveal that the conserved E3 ubiquitin ligase PHR (PAM, highwire Rpm-1) controls a regulatory protein degradation pathway essential both for axonal targeting during embryonic development as well as for the proper formation and function of neuron muscular junctions (NMJ).     

Angelman Syndrome Protein Ube3a Regulates Synaptic Growth and Endocytosis by Inhibiting BMP Signaling in Drosophila

Altered expression of the E3 ubiquitin ligase UBE3A, which is involved in protein degradation through the proteasome-mediated pathway, is associated with neurodevelopmental and behavioral defects observed in Angelman syndrome (AS) and autism. However, little is known about the neuronal function of UBE3A and the pathogenesis of UBE3A-associated disorders. To understand the in vivo function of UBE3A in the nervous system, we generated multiple mutations of ube3a, the Drosophila ortholog of UBE3A. We found a significantly increased number of total boutons and satellite boutons in conjunction with compromised endocytosis in the neuromuscular junctions (NMJs) of ube3a mutants compared to the wild type. Genetic and biochemical analysis showed upregulation of bone morphogenetic protein (BMP) signaling in the nervous system of ube3a mutants. An immunochemical study revealed a specific increase in the protein level of Thickveins (Tkv), a type I BMP receptor, but not other BMP receptors Wishful thinking (Wit) and Saxophone (Sax), in ube3a mutants. Ube3a was associated with and specifically ubiquitinated lysine 227 within the cytoplasmic tail of Tkv, and promoted its proteasomal degradation in Schneider 2 cells. Negative regulation of Tkv by Ube3a was conserved in mammalian cells. These results reveal a critical role for Ube3a in regulating NMJ synapse development by repressing BMP signaling. This study sheds new light onto the neuronal functions of UBE3A and provides novel perspectives for understanding the pathogenesis of UBE3A-associated disorders.     

SUMO on the road to neurodegeneration

Sumoylation is a post-translational modification by which small ubiquitin-like modifiers (SUMO) are covalently conjugated to target proteins. This reversible pathway provides a rapid and efficient way to modulate the subcellular localization, activity and stability of a wide variety of substrates. Similar to its well-known cousin ubiquitin, SUMO co-localize with the neuronal inclusions associated with several neurodegenerative diseases, including multiple system atrophy, Huntington's disease and other related polyglutamine disorders. The identification of huntingtin, ataxin-1, tau and alpha-synuclein as SUMO substrates further supports the involvement of sumoylation in the pathogenesis of this family of neurological diseases. In addition to direct targeting of these constituent proteins, sumoylation also impacts other disease pathways such as oxidative stress, protein aggregation and proteasome-mediated degradation. This review highlights the recent advances in understanding the contributions of SUMO to neurodegeneration and the underlying pathogenic mechanisms of these diseases.     

转录调节因子TORCs的研究进展及其参与神经保护作用的展望

随着基础研究的深入,人们对于cAMP反应元件结合蛋白（cAMP response element binding protein,CREB）及其家族的功能了解越来越多。在多种细胞中,这些转录因子作为效应分子介导细胞外环境变化所引起基因表达和长时程生理功能改变。存神经系统,许多胞外信号,包括细胞膜去极化、膜受体通道开放以及神经损伤等,都可以引起CREB及其家族成员分子的激活,从而引起CREB依赖的基因转录。CREB的激活及其下游綦因的转录在多种复杂的发育、神经可塑性和病理过程中都具有十分重要的作用。TORCs（transducers of regulated CREB）是新近被发现的一类CREB的共激活列子,但其对CREB的精确调控机制尚不明确。目前已知TORCs可以促进CREB依赖的基因转录,并且这种增强作用不依赖于CREB丝氨酸133位点的磷酸化,而足增加CREB和其辅助因子的结合,从而实现其下游基因在启动予水平的活性增加。在神经系统的各类疾病中,CREB对于促进神经元存活、再生、细胞修复等过程具有十分重要的作用。因此,作为CREB的共激活因子,TORCS在神经损伤修复中也具有潜在作用,本文主要针对新近发现的CREB共激活因了TORCs进行简要的文献综述和其在神经保护作用中的展望。