共查询到20条相似文献,搜索用时 15 毫秒
1.
Mitochondrial dysfunctions are a known pathogenetic mechanism of a number of neurological and psychiatric disorders. At the same time, mutations in genes encoding for components of the mitochondrial respiratory chain cause mitochondrial diseases, which commonly exhibit neurological symptoms. Mitochondria are therefore critical for the functionality of the human nervous system. The importance of mitochondria stems from their key roles in cellular metabolism, calcium handling, redox and protein homeostasis, and overall cellular homeostasis through their dynamic network. Here, we describe how the use of pluripotent stem cells (PSCs) may help in addressing the physiological and pathological relevance of mitochondria for the human nervous system. PSCs allow the generation of patient-derived neurons and glia and the identification of gene-specific and mutation-specific cellular phenotypes via genome engineering approaches. We discuss the recent advances in PSC-based modeling of brain diseases and the current challenges of the field. We anticipate that the careful use of PSCs will improve our understanding of the impact of mitochondria in neurological and psychiatric disorders and the search for effective therapeutic avenues. 相似文献
2.
Neurons have highly specialized intracellular compartments that facilitate the development and activity of the nervous system. Ubiquitination is a post-translational modification that controls many aspects of neuronal function by regulating protein abundance. Disruption of this signaling pathway has been demonstrated in neurological disorders such as Parkinson’s disease, Amyotrophic Lateral Sclerosis and Angleman Syndrome. Since many neurological disorders exhibit ubiquitinated protein aggregates, the loss of neuronal ubiquitin homeostasis may be an important contributor of disease. This review discusses the mechanisms utilized by neurons to control the free pool of ubiquitin necessary for normal nervous system development and function as well as new roles of protein ubiquitination in regulating the synaptic activity. 相似文献
3.
We re-annotated the interacting partners of the neuronal scaffold protein DISC1 using a knowledge-based approach that incorporated recent protein interaction data and published literature to. This revealed two highly connected networks. These networks feature cellular function and maintenance, and cell signaling. Of potentially greatest interest was the novel finding of a high degree of connectivity between the DISC1 scaffold protein, linked to psychiatric illness, and huntingtin, the protein which is mutated in Huntington's disease. The potential link between DISC1, huntingtin and their interacting partners may open new areas of research into the effects of pathway dysregulation in severe neurological disorders. 相似文献
4.
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. 相似文献
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《Cell cycle (Georgetown, Tex.)》2013,12(20):3452-3460
Bioenergy homeostasis constitutes one of the most crucial foundations upon which other cellular and organismal processes may be executed. AMP-activated protein kinase (AMPK) has been shown to be the key player in the regulation of energy metabolism, and thus is becoming the focus of research on obesity, diabetes and other metabolic disorders. However, its role in the brain, the most energy-consuming organ in our body, has only recently been studied and appreciated. Widely expressed in the brain, AMPK activity is tightly coupled to the energy status at both neuronal and whole-body levels. Importantly, AMPK signaling is intimately implicated in multiple aspects of brain development and function including neuronal proliferation, migration, morphogenesis and synaptic communication, as well as in pathological conditions such as neuronal cell death, energy depletion and neurodegenerative disorders. 相似文献
8.
D F Horrobin C N Bennett 《Prostaglandins, leukotrienes, and essential fatty acids》1999,60(3):141-167
Phospholipids make up about 60% of the brain's dry weight. In spite of this, phospholipid metabolism has received relatively little attention from those seeking genetic factors involved in psychiatric and neurological disorders. However, there is now increasing evidence from many quarters that abnormal phospholipid and related fatty acid metabolism may contribute to illnesses such as schizophrenia, bipolar disorder, depression and attention deficit hyperactivity disorder. To date the possible specific proteins and genes involved have been relatively ill-defined. This paper reviews the main pathways of phospholipid metabolism, emphasizing the roles of phospholipases of the A2 and C series in signal transduction processes. It identifies some likely protein candidates for involvement in psychiatric and neurological disorders. It also reviews the chromosomal locations of regions likely to be involved in these disorders, and relates these to the known locations of genes directly or indirectly involved in phospholipid and fatty acid metabolism. 相似文献
9.
《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2020,1867(9):118745
Glycogen synthase kinase 3beta (GSK-3β) is an enzyme with a variety of cellular functions in addition to the regulation of glycogen metabolism. In the central nervous system, different intracellular signaling pathways converge on GSK-3β through a cascade of phosphorylation events that ultimately control a broad range of neuronal functions in the development and adulthood. In mice, genetically removing or increasing GSK-3β cause distinct functional and structural neuronal phenotypes and consequently affect cognition. Precise control of GSK-3β activity is important for such processes as neuronal migration, development of neuronal morphology, synaptic plasticity, excitability, and gene expression. Altered GSK-3β activity contributes to aberrant plasticity within neuronal circuits leading to neurological, psychiatric disorders, and neurodegenerative diseases. Therapeutically targeting GSK-3β can restore the aberrant plasticity of neuronal networks at least in animal models of these diseases. Although the complete repertoire of GSK-3β neuronal substrates has not been defined, emerging evidence shows that different ion channels and their accessory proteins controlling excitability, neurotransmitter release, and synaptic transmission are regulated by GSK-3β, thereby supporting mechanisms of synaptic plasticity in cognition. Dysregulation of ion channel function by defective GSK-3β activity sustains abnormal excitability in the development of epilepsy and other GSK-3β-linked human diseases. 相似文献
10.
Huntington's disease (HD) is a hereditary neurodegenerative disorder that gradually robs sufferers of the ability to control movements and induces psychological and cognitive impairments. This devastating, lethal disease is one of several neurological disorders caused by trinucleotide expansions in affected genes, including spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, and spinal bulbar muscular atrophy. HD symptoms are associated with region-specific neuronal loss within the central nervous system, but to date the mechanism of this selective cell death remains unknown. Strong evidence from studies in humans and animal models suggests the involvement of energy metabolism defects, which may contribute to excitotoxic processes, oxidative dmage, and altered gene regulation. The development of transgenic mouse models expressing the human HD mutation has provided novel opportunities to explore events underlying selective neuronal death in HD, which has hitherto been impossible in humans. Here we discuss how animal models are redefining the role of energy metabolism in HD etiology. 相似文献
11.
Hideyuki Okano Atsushi Miyawaki Kiyoto Kasai 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2015,370(1668)
There is an emerging interest in brain-mapping projects in countries across the world, including the USA, Europe, Australia and China. In 2014, Japan started a brain-mapping project called Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS). Brain/MINDS aims to map the structure and function of neuronal circuits to ultimately understand the vast complexity of the human brain, and takes advantage of a unique non-human primate animal model, the common marmoset (Callithrix jacchus). In Brain/MINDS, the RIKEN Brain Science Institute acts as a central institute. The objectives of Brain/MINDS can be categorized into the following three major subject areas: (i) structure and functional mapping of a non-human primate brain (the marmoset brain); (ii) development of innovative neurotechnologies for brain mapping; and (iii) human brain mapping; and clinical research. Brain/MINDS researchers are highly motivated to identify the neuronal circuits responsible for the phenotype of neurological and psychiatric disorders, and to understand the development of these devastating disorders through the integration of these three subject areas. 相似文献
12.
Takuya Kumamoto Marie Nakajima Reina Uga Naoko Ihayazaka Haruna Kashihara Kazuaki Katakawa Tsutomu Ishikawa Ryotaro Saiki Kazuhiro Nishimura Kazuei Igarashi 《Bioorganic & medicinal chemistry》2018,26(3):603-608
N-Methyl-d-aspartate (NMDA) receptors have been implicated in learning and memory, and may also play a central role in various conditions leading to neuronal degradation. NMDA receptor antagonists could therefore be of therapeutic benefit for a number of neurological disorders. We have designed hybrid compounds of polyamines and memantine, both of which function as NMDA channel blockers. The triamine derivative with a guanidine moiety showed more potent antagonistic activity than memantine. 相似文献
13.
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a mutation in the gene huntingtin and characterized by motor, cognitive and psychiatric symptoms. Huntingtin contains a CAG repeat in exon 1. An expansion of this CAG repeat above 35 results in misfolding of Huntingtin, giving rise to protein aggregates and neuronal cell death. There are several transgenic HD mouse models that reproduce most of the features of the human disorder, for example protein inclusions, some neurodegeneration as well as motor and cognitive symptoms. At the same time, a subgroup of the HD transgenic mouse models exhibit dramatically reduced susceptibility to excitotoxicity. The mechanism behind this is unknown. Here, we review the literature regarding this phenomenon, attempt to explain what protein domains are crucial for this phenomenon and point toward a putative mechanism. We suggest, that the C-terminal domain of exon 1 Huntingtin, namely the proline rich domain, is responsible for mediating a neuroprotective effect against excitotoxicity. Furthermore, we point out the possible importance of this mechanism for future therapies in neurological disorders that have been suggested to be associated with excitotoxicity, for example Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. 相似文献
14.
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. 相似文献
15.
Joice Stipursky Tania Cristina Leite de Sampaio e Spohr Vivian Oliveira Sousa Flávia Carvalho Alcantara Gomes 《Neurochemical research》2012,37(11):2402-2418
Neuron–astroglia interactions play a key role in several events of brain development, such as neuronal generation, migration, survival, and differentiation; axonal growth; and synapse formation and function. While there is compelling evidence of the effects of astrocyte factors on neurons, their effects on astrocytes have not been fully determined. In this review, we will focus on the role of neurons in astrocyte generation and maturation. Further, we highlight the great heterogeneity and diversity of astroglial and neural progenitors such as radial glia cells, and discuss the importance of the variety of cellular interactions in controlling the structural and functional organization of the brain. Finally, we present recent data on a new role of astrocytes in neuronal maturation, as mediators of the action of biolipids in the cerebral cortex. We will argue that the functional architecture of the brain depends on an intimate neuron-glia partnership, by briefly discussing the emerging view of how neuron-astrocyte dysfunctions might be associated with neurodegenerative diseases and neurological disorders. 相似文献
16.
Disrupted in Schizophrenia 1 (DISC1) is a key susceptibility gene for major psychiatric disorders. DISC1 plays a role in key neuronal processes such as neuronal proliferation, migration, integration and function via DISC1's roles at the centrosome and synapse, and in the regulation of intracellular signaling pathways. Recently, the idea of protein aggregation as a disease mechanism for DISC1 has been suggested. In our recent paper we explore these DISC1 protein aggregates in cell lines and neurons and find they are recruited to the aggresome and cause disruption of DISC1 function in intracellular transport. 相似文献
17.
Akansha Mohan Aaron J. Roberto Abhishek Mohan Aileen Lorenzo Kathryn Jones Martin J. Carney Luis Liogier-Weyback Soonjo Hwang Kyle A.B. Lapidus 《The Yale journal of biology and medicine》2016,89(1):49-57
The relationship of cortical structure and specific neuronal circuitry to global brain function, particularly its perturbations related to the development and progression of neuropathology, is an area of great interest in neurobehavioral science. Disruption of these neural networks can be associated with a wide range of neurological and neuropsychiatric disorders. Herein we review activity of the Default Mode Network (DMN) in neurological and neuropsychiatric disorders, including Alzheimer’s disease, Parkinson’s disease, Epilepsy (Temporal Lobe Epilepsy - TLE), attention deficit hyperactivity disorder (ADHD), and mood disorders. We discuss the implications of DMN disruptions and their relationship to the neurocognitive model of each disease entity, the utility of DMN assessment in clinical evaluation, and the changes of the DMN following treatment. 相似文献
18.
The brain is the most lipid-rich organ in the body and, owing to the impermeable nature of the blood-brain barrier, lipid and lipoprotein metabolism within this organ is distinct from the rest of the body. Apolipoproteins play a well-established role in the transport and metabolism of lipids within the CNS; however, evidence is emerging that they also fulfill a number of functions that extend beyond lipid transport and are critical for healthy brain function. The importance of apolipoproteins in brain physiology is highlighted by genetic studies, where apolipoprotein gene polymorphisms have been identified as risk factors for several neurological diseases. Furthermore, the expression of brain apolipoproteins is significantly altered in several brain disorders. The purpose of this article is to provide an up-to-date assessment of the major apolipoproteins found in the brain (ApoE, ApoJ, ApoD and ApoA-I), covering their proposed roles and the factors influencing their level of expression. Particular emphasis is placed on associations with neurological and psychiatric disorders. 相似文献
19.
《Autophagy》2013,9(5):851-852
Disrupted in Schizophrenia 1 (DISC1) is a key susceptibility gene for major psychiatric disorders. DISC1 plays a role in key neuronal processes such as neuronal proliferation, migration, integration and function via DISC1's roles at the centrosome and synapse, and in the regulation of intracellular signaling pathways. Recently, the idea of protein aggregation as a disease mechanism for DISC1 has been suggested. In our recent paper we explore these DISC1 protein aggregates in cell lines and neurons and find they are recruited to the aggresome and cause disruption of DISC1 function in intracellular transport. 相似文献
20.
Xenobiotic metabolizing enzymes in the central nervous system: Contribution of cytochrome P450 enzymes in normal and pathological human brain 总被引:2,自引:1,他引:1
The metabolism of xenobiotics in human brain constitutes a field of recent intensive research in relation to the potential implications in the pharmacological effect of drugs acting on the central nervous system. Cytochrome P450 enzymes (CYPs) play a crucial role in these metabolic pathways and the existence of functional CYP monooxygenases in brain is now well established. These enzymes are preferentially localized in the neuronal cells within the microsomal fraction and the inner membrane of mitochondria. Although low, the metabolism in situ could influence individual response to xenobiotics or produce reactive, toxic metabolites causing irreversible damage in the neuronal cells. The abundant presence of CYPs in selective cell populations within different regions of the brain has also suggested a role for these enzymes in brain physiology thus not restricted to xenobiotic-induced neurotoxicity. For instance, CYPs participate in the regulation of neurotransmitters and steroids and brain maintenance of cholesterol homeostasis. Recent advances support an additional role for these enzymes in the pathogenesis of psychiatric and neurodegenerative disorders such as depression, schizophrenia, and Alzheimer's and Parkinson's diseases. The characterization of brain CYP isoforms and their localization, the identification of their substrates and metabolic end-products will allow better understanding of the role of these enzymes in brain physiology, development and diseases. 相似文献