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1.
Amyloid β-induced FOXRED2 mediates neuronal cell death via inhibition of proteasome activity 总被引:1,自引:1,他引:0
Proteasome inhibition has been regarded as one of the mediators of Aβ neurotoxicity. In this study, we found that FOXRED2,
a novel endoplasmic reticulum (ER) residential protein, is highly up-regulated by Aβ in rat cortical neurons and SH-SY5Y cells.
Over-expression of FOXRED2 inhibits proteasome activity in the microsomal fractions containing ER and interferes with proteasome
assembly, as evidenced by gel filtration and native gel electrophoresis analysis. In contrast, reduced expression of FOXRED2
rescues Aβ-induced inhibition of proteasome activity. FOXRED2 is an unstable protein with two degradation boxes and one KEN
box, and its N-terminal oxidoreductase domain is required for proteasome inhibition. Ectopic expression of FOXRED2 induces
ER stress-mediated cell death via caspase-12, which is inhibited by Salubrinal. Further, down-regulation of FOXRED2 expression
attenuates Aβ-induced cell death and the ER stress response. These results suggest that up-regulated FOXRED2 inhibits proteasome
activity by interfering with 26S proteasome assembly to contribute to Aβ neurotoxicity via an ER stress response. 相似文献
2.
Hobson SA Bacon A Elliot-Hunt CR Holmes FE Kerr NC Pope R Vanderplank P Wynick D 《Cellular and molecular life sciences : CMLS》2008,65(12):1806-1812
The neuropeptide galanin is widely, but not ubiquitously, expressed in the adult nervous system. Its expression is markedly upregulated in many neuronal tissues after nerve injury or disease. Over the last 10 years we have demonstrated that the peptide plays a developmental survival role to subsets of neurons in the peripheral and central nervous systems with resulting phenotypic changes in neuropathic pain and cognition. Galanin also appears to play a trophic role to adult sensory neurons following injury, via activation of GalR2, by stimulating neurite outgrowth. Furthermore, galanin also plays a neuroprotective role to the hippocampus following excitotoxic injury, again mediated by activation of GalR2. In summary, these studies demonstrate that a GalR2 agonist might have clinical utility in a variety of human diseases that affect the nervous system. 相似文献
3.
Galanin – 25 years with a multitalented neuropeptide 总被引:2,自引:0,他引:2
Galanin (GAL) and GAL receptors (GALRs) are overexpressed in degenerating brain regions associated with cognitive decline in Alzheimer's disease (AD). The functional consequences of GAL plasticity in AD are unclear. GAL inhibits cholinergic transmission in the hippocampus and impairs spatial memory in rodent models, suggesting GAL overexpression exacerbates cognitive impairment in AD. By contrast, gene expression profiling of individual cholinergic basal forebrain (CBF) neurons aspirated from AD tissue revealed that GAL hyperinnervation positively regulates mRNAs that promote CBF neuronal function and survival. GAL also exerts neuroprotective effects in rodent models of neurotoxicity. These data support the growing concept that GAL overexpression preserves CBF neuron function which in turn may slow the onset of AD symptoms. Further elucidation of GAL activity in selectively vulnerable brain regions will help gauge the therapeutic potential of GALR ligands for the treatment of AD. 相似文献
4.
W. B. Kristan Jr G. Wittenberg M. P. Nusbaum W. Stern-Tomlinson 《Cellular and molecular life sciences : CMLS》1988,44(5):383-389
Summary We are using the medicinal leech to study the neuronal basis of behavioral choice. In particular, we are recording from neurons, both extracellularly and intracellularly, in preparations that can express three different behaviors: the shortening reflex, crawling and swimming. We have found that particular mechanosensory neurons can elicit any of the behaviors, and that the movements are produced by just four sets of muscles, each controlled by a small number of motor neurons. Hence, there must be three different pattern-generating neuronal circuits, each of which can be activated by the same set of sensory neurons. We are studying how the choice is made among the three behaviors by recording, while one behavior is being performed, from neurons known to be involved in the initiation of the other two. We have found that an interneuron, cell 204, which is known to initiate and maintain swimming, is also active during shortening and crawling. The activity level in this interneuron can influence whether a mechanosensory stimulus produces shortening or swimming. The neuronal mechanisms by which this choice is normally effected awaits further elucidation of the circuits that elicit and generate shortening and crawling. 相似文献
5.
We are using the medicinal leech to study the neuronal basis of behavioral choice. In particular, we are recording from neurons, both extracellularly and intracellularly, in preparations that can express three different behaviors: the shortening reflex, crawling and swimming. We have found that particular mechanosensory neurons can elicit any of the behaviors, and that the movements are produced by just four sets of muscles, each controlled by a small number of motor neurons. Hence, there must be three different pattern-generating neuronal circuits, each of which can be activated by the same set of sensory neurons. We are studying how the choice is made among the three behaviors by recording, while one behavior is being performed, from neurons known to be involved in the initiation of the other two. We have found that an interneuron, cell 204, which is known to initiate and maintain swimming, is also active during shortening and crawling. The activity level in this interneuron can influence whether a mechanosensory stimulus produces shortening or swimming. The neuronal mechanisms by which this choice is normally effected awaits further elucidation of the circuits that elicit and generate shortening and crawling. 相似文献
6.
Axon degeneration is a pathophysiological process of axonal dying and breakdown, which is characterized by several morphological features including the accumulation of axoplasmic organelles, disassembly of microtubules, and fragmentation of the axonal cytoskeleton. Autophagy, a highly conserved lysosomal-degradation machinery responsible for the control of cellular protein quality, is widely believed to be essential for the maintenance of axonal homeostasis in neurons. In recent years, more and more evidence suggests that dysfunctional autophagy is associated with axonal degeneration in many neurodegenerative diseases. Here, we review the core machinery of autophagy in neuronal cells, and provide several major steps that interfere with autophagy flux in neurodegenerative conditions. Furthermore, this review highlights the potential role of neuronal autophagy in axon degeneration, and presents some possible molecular mechanisms by which dysfunctional autophagy leads to axon degeneration in pathological conditions. 相似文献
7.
8.
Cheung NS Choy MS Halliwell B Teo TS Bay BH Lee AY Qi RZ Koh VH Whiteman M Koay ES Chiu LL Zhu HJ Wong KP Beart PM Cheng HC 《Cellular and molecular life sciences : CMLS》2004,61(15):1926-1934
The tumor suppressor function of PTEN is attributed to its phospholipid phosphatase activity that
dephosphorylates the plasma membrane phosphatidylinositol-(3,4,5)-triphosphate
[PtdIns(3,4,5)P3]. Implicit in this notion is that PTEN needs to be targeted to the plasma
membrane to dephosphorylate PtdIns(3,4,5)P3. However, the recruitment of PTEN to the plasma
membrane is not fully understood. Here, we demonstrate PTEN accumulation in the detergent-insoluble fraction of
neuronal cells in response to treatment by the proteasome inhibitor lactacystin. First, lactacystin induces
apoptosis and the activation of caspase-3 in cultured cortical neurons. Second, PTEN undergoes proteolysis to
form a truncated 50-kDa form that lacks parts of its C-terminal tail. Third, the truncated PTEN is stably
associated with the detergent-insoluble fraction in which the plasma membrane marker protein flotillin-1 resides.
Taken together, our results suggest that truncation and accumulation of PTEN to the detergent-insoluble membrane
fraction are two events associated with the apoptotic signals of the proteasome inhibitor in cortical neurons.Received 24 March 2004; received after revision 26 May 2004; accepted 5 June 2004 相似文献
9.
Chronic gestational exposure to ethanol impairs insulin-stimulated survival and mitochondrial function in cerebellar neurons 总被引:6,自引:1,他引:5
Chronic gestational exposure to ethanol has profound adverse effects on brain development. In this regard, studies using
in vitro models of ethanol exposure demonstrated impaired insulin signaling mechanisms associated with increased apoptosis
and reduced mitochondrial function in neuronal cells. To determine the relevance of these findings to fetal alcohol syndrome,
we examined mechanisms of insulin-stimulated neuronal survival and mitochondrial function using a rat model of chronic gestational
exposure to ethanol. In ethanol-exposed pups, the cerebellar hemispheres were hypoplastic and exhibited increased apoptosis.
Isolated cerebellar neurons were cultured to selectively evaluate insulin responsiveness. Gestational exposure to ethanol
inhibited insulin-stimulated neuronal viability, mitochondrial function, Calcein AM retention (membrane integrity), and GAPDH
expression, and increased dihydrorosamine fluorescence (oxidative stress) and pro-apoptosis gene expression (p53, Fas-receptor,
and Fas-ligand). In addition, neuronal cultures generated from ethanol-exposed pups had reduced levels of insulin-stimulated
Akt, GSK-3β, and BAD phosphorylation, and increased levels of non-phosphorylated (activated) GSK-3β and BAD protein expression.
The aggregate results suggest that insulin-stimulated central nervous system neuronal survival mechanisms are significantly
impaired by chronic gestational exposure to ethanol, and that the abnormalities in insulin signaling mechanisms persist in
the early postnatal period, which is critical for brain development.
Received 21 January 2002; received after revision 28 February 2002; accepted 25 March 2002 相似文献
10.
J proteins are chief regulators of the Hsp70 family, a highly conserved family of ATPases that mediate conformational changes in a broad range of proteins. The J protein family has been the central focus of numerous prokaryote and eukaryote biologists. Common questions that arise include: How does the J protein/Hsp70 machinery support protein folding? What role do J proteins play in protein misfolding and neurodegenerative disorders? Can the J protein/ Hsp70 machinery be harnessed to provide a rational basis for recombinant protein production? The current progress that has resulted from the convergence of biochemistry with Escherichia coli and Saccharomyces cerevisiae genetics has accelerated the pace at which these questions are being elucidated. We are beginning to gain some insights into the neuronal network of J proteins. Here, we highlight recent advances in our understanding of how select J proteins harness Hsp70 s for fundamentally important conformational work in neurons. 相似文献
11.
Tae-In Kam Youngdae Gwon Yong-Keun Jung 《Cellular and molecular life sciences : CMLS》2014,71(24):4803-4813
Alzheimer’s disease (AD) is the most common neurodegenerative disease. Although a major cause of AD is the accumulation of amyloid-β (Aβ) peptide that induces neuronal loss and cognitive impairments, our understanding of its neurotoxic mechanisms is limited. Recent studies have identified putative Aβ-binding receptors that mediate Aβ neurotoxicity in cells and models of AD. Once Aβ interacts with a receptor, a toxic signal is transduced into neurons, resulting in cellular defects including endoplasmic reticulum stress and mitochondrial dysfunction. In addition, Aβ can also be internalized into neurons through unidentified Aβ receptors and induces malfunction of subcellular organelles, which explains some part of Aβ neurotoxicity. Understanding the neurotoxic signaling initiated by Aβ-receptor binding and cellular defects provide insight into new therapeutic windows for AD. In the present review, we summarize the findings on Aβ-binding receptors and the neurotoxicity of oligomeric Aβ. 相似文献
12.
Pierfrancesco Pagella Lucia Jiménez-Rojo Thimios A. Mitsiadis 《Cellular and molecular life sciences : CMLS》2014,71(12):2241-2251
The head is innervated by 12 cranial nerves (I–XII) that regulate its sensory and motor functions. Cranial nerves are composed of sensory, motor, or mixed neuronal populations. Sensory neurons perceive generally somatic sensations such as pressure, pain, and temperature. These neurons are also involved in smell, vision, taste, and hearing. Motor neurons ensure the motility of all muscles and glands. Innervation plays an essential role in the development of the various orofacial structures during embryogenesis. Hypoplastic cranial nerves often lead to abnormal development of their target organs and tissues. For example, Möbius syndrome is a congenital disease characterized by defective innervation (i.e., abducens (VI) and facial (VII) nerves), deafness, tooth anomalies, and cleft palate. Hence, it is obvious that the peripheral nervous system is needed for both development and function of orofacial structures. Nerves have a limited capacity to regenerate. However, neural stem cells, which could be used as sources for neural tissue maintenance and repair, have been found in adult neuronal tissues. Similarly, various adult stem cell populations have been isolated from almost all organs of the human body. Stem cells are tightly regulated by their microenvironment, the stem cell niche. Deregulation of adult stem cell behavior results in the development of pathologies such as tumor formation or early tissue senescence. It is thus essential to understand the factors that regulate the functions and maintenance of stem cells. Yet, the potential importance of innervation in the regulation of stem cells and/or their niches in most organs and tissues is largely unexplored. This review focuses on the potential role of innervation in the development and homeostasis of orofacial structures and discusses its possible association with stem cell populations during tissue repair. 相似文献
13.
Leung JY Bennett WR Herbert RP West AK Lee PR Wake H Fields RD Chuah MI Chung RS 《Cellular and molecular life sciences : CMLS》2012,69(5):809-817
Prior studies have reported that metallothionein I/II (MT) promote regenerative axonal sprouting and neurite elongation of
a variety of central nervous system neurons after injury. In this study, we evaluated whether MT is capable of modulating
regenerative axon outgrowth of neurons from the peripheral nervous system. The effect of MT was firstly investigated in dorsal
root ganglion (DRG) explants, where axons were scratch-injured in the presence or absence of exogenous MT. The application
of MT led to a significant increase in regenerative sprouting of neurons 16 h after injury. We show that the pro-regenerative
effect of MT involves an interaction with the low-density lipoprotein receptor megalin, which could be blocked using the competitive
antagonist RAP. Pre-treatment with the mitogen-activated protein kinase (MAPK) inhibitor PD98059 also completely abrogated
the effect of exogenous MT in promoting axonal outgrowth. Interestingly, we only observed megalin expression in neuronal soma
and not axons in the DRG explants. To investigate this matter, an in vitro injury model was established using Campenot chambers,
which allowed the application of MT selectively into either the axonal or cell body compartments after scratch injury was
performed to axons. At 16 h after injury, regenerating axons were significantly longer only when exogenous MT was applied
solely to the soma compartment, in accordance with the localized expression of megalin in neuronal cell bodies. This study
provides a clear indication that MT promotes axonal regeneration of DRG neurons, via a megalin- and MAPK-dependent mechanism. 相似文献
14.
Odor maps in the brain: Spatial aspects of odor representation in sensory surface and olfactory bulb
Korsching SI 《Cellular and molecular life sciences : CMLS》2001,58(4):520-530
The olfactory sense detects and distinguishes a multitude of different odors. Recent progress in molecular as well as physiological approaches has elucidated basic principles of neuronal encoding of odorants, common to insects and vertebrates. The construction of neuronal representations for odors begins with the task of mapping the multidimensional odor space onto the two-dimensional sensory surface, and subsequently onto the olfactory bulb or antennal lobe. A distributed expression of odorant receptors, albeit restricted to subregions of the sensory surface (large, intermediate or small for zebrafish, mouse or drosophila, respectively), ensures a robust representation, insensitive to mechanical insult. Olfactory receptor neurons expressing the same odorant receptors converge to form a receptotopic map in the olfactory bulb or antennal lobe. The emerging coding principle is a chemotopic representation of odorants at the first brain level, realized either as combinatorial or as monospecific representation, depending on the odorant. 相似文献
15.
Vitamin-B12 is a generic term for corrinoid compounds that exhibit the biological activity of cyanocobalamin and are collectively referred
to as cobalamins. Methylcobalamin and 5-deoxyadenosylcobalamin are the active cobalamins in human metabolism. Cobalamin plays
a crucial role in the maintenance of homocysteine and methylmalonyl-CoA homeostasis and is required for erythrocyte formation
and DNA synthesis. Data from human and animal studies indicate that cobalamin deficiency impairs neuronal function; a process
that is thought to contribute to age-related cognitive decline and dementia. Cobalamin deficiency also results in dysfunction
of the peripheral nervous system; among other disorders. Although there is a detailed understanding of the biochemical pathways
that are perturbed in cobalamin deficiency, the mechanisms underlying age-related dyshomeostasis in such pathways remain to
be addressed. Because cobalamin utilization is dependent on its efficient transit through lysosomes, and mounting evidence
indicates that lysosomal function deteriorates in aging long-lived post-mitotic cells such as neurons, in the present article
we review published data that supports the proposition that impaired lysosomal processing of cobalamin may play a significant
role in age-related (neuro) degenerative diseases. 相似文献
16.
17.
Alexandra V. Andreeva Mikhail A. Kutuzov 《Cellular and molecular life sciences : CMLS》2009,66(19):3103-3110
PPEF/PP7 represents one of the five subfamilies of the PPP protein Ser/Thr phosphatases. Studies published in recent years
point to a role of plant PP7 at a crossroad of different pathways of light and stress signalling. In animals, PPEFs are highly
expressed in sensory neurons, and Drosophila PPEF phosphatase, rdgC, is essential for dephosphorylation of rhodopsin. Expression profiling suggests that mammalian PPEF
may play a role in stress-protective responses, cell survival, growth, proliferation, and oncogenesis. Despite structural
similarities of the catalytic domains and the fact that some of these phosphatases are involved in light perception both in
animals and in plants, the plant and non-plant representatives of this group have distinct domain architecture and appear
not to be orthologues. 相似文献
18.
19.
Linxia Zhang Linsey C. Seitz Amy M. Abramczyk Li Liu Christina Chan 《Cellular and molecular life sciences : CMLS》2011,68(5):863-876
The intracellular second messenger cAMP is frequently used in induction media to induce mesenchymal stem cells (MSCs) into
neural lineage cells. To date, an understanding of the role cAMP exerts on MSCs and whether cAMP can induce MSCs into functional
neurons is still lacking. We found cAMP initiated neuron-like morphology changes early and neural differentiation much later.
The early phase changes in morphology were due to cell shrinkage, which subsequently rendered some cells apoptotic. While
the morphology changes occurred prior to the expression of neural markers, it is not required for neural marker expression
and the two processes are differentially regulated downstream of cAMP-activated protein kinase A. cAMP enabled MSCs to gain
neural marker expressions with neuronal function, such as, calcium rise in response to neuronal activators, dopamine, glutamate,
and potassium chloride. However, only some of the cells induced by cAMP responded to the three neuronal activators and further
lack the neuronal morphology, suggesting that although cAMP is able to direct MSCs towards neural differentiation, they do
not achieve terminal differentiation. 相似文献
20.
Formation of myelin sheaths by Schwann cells (SCs) enables rapid and efficient transmission of action potentials in peripheral axons, and disruption of myelination results in disorders that involve decreased sensory and motor functions. Given that construction of SC myelin requires high levels of lipid and protein synthesis, mitochondria, which are pivotal in cellular metabolism, may be potential regulators of the formation and maintenance of SC myelin. Supporting this notion, abnormal mitochondria are found in SCs of neuropathic peripheral nerves in both human patients and the relevant animal models. However, evidence for the importance of SC mitochondria in myelination has been limited, until recently. Several studies have recently used genetic approaches that allow SC-specific ablation of mitochondrial metabolic activity in living animals to show the critical roles of SC mitochondria in the development and maintenance of peripheral nerve axons. Here, we review current knowledge about the involvement of SC mitochondria in the formation and dysfunction of myelinated axons in the peripheral nervous system. 相似文献