35 research outputs found
Iron entry in neurons and astrocytes: a link with synaptic activity
No full textIron plays a fundamental role in the development of the central nervous system (CNS) as well as in several neuronal functions including synaptic plasticity. Accordingly, neuronal iron supply is tightly controlled: it depends not only on transferrin-bound iron but also on non-transferrin-bound iron (NTBI), which represents a relevant quote of the iron physiologically present in the cerebrospinal fluid (CSF). Different calcium permeable channels as well as the divalent metal transporter 1 (DMT1) have been proposed to sustain NTBI entry in neurons and astrocytes even though it remains an open issue. In both cases, it emerges that the control of iron entry is tightly linked to synaptic activity. The iron-induced oxidative tone can, in physiological conditions, positively influence the calcium levels and thus the synaptic plasticity. On the other hand, an excess of iron, with the ensuing uncontrolled production of reactive oxygen species (ROS), is detrimental for neuronal survival. A protective mechanism can be played by astrocytes that, more resistant to oxidative stress, can uptake iron, thereby buffering its concentration in the synaptic environment. This competence is potentiated when astrocytes undergo activation during neuroinflammation and neurodegenerative processes. In this minireview we focus on the mechanisms responsible for NTBI entry in neurons and astrocytes and on how they can be modulated during synaptic activity. Finally, we speculate on the relevance they may have in both physiological and pathological conditions
eIF4B phosphorylation at Ser504 links synaptic activity with protein translation in physiology and pathology
No full textAbstractNeuronal physiology requires activity-driven protein translation, a process in which translation initiation factors are key players. We focus on eukaryotic initiation factor 4B (eIF4B), a regulator of protein translation, whose function in neurons is undetermined. We show that neuronal activity affects eIF4B phosphorylation and identify Ser504 as a phosphorylation site regulated by casein kinases and sensitive to the activation of metabotropic glutamate receptors. Ser504 phosphorylation increases eIF4B recruitment to the pre-initiation complex and influences eIF4B localization at synapses. Moreover, Ser504 phosphorylation modulates the translation of protein kinase Mζ. Therefore, by sensing synaptic activity, eIF4B could adjust translation to neuronal needs, promoting adaptive changes in synaptic plasticity. We also show that Ser504 phosphorylation is increased in vivo in a rat model of epilepsy during epileptogenesis i.e. when translation drives maladaptive synaptic changes. We propose eIF4B as a mediator between neuronal activity and translation, with relevance in the control of synaptic plasticity.</jats:p
Astrocytes acquire resistance to iron-dependent oxidative stress upon proinflammatory activation
No full textBackground: Astrocytes respond to local insults within the brain and the spinal cord with important changes in their phenotype. This process, overall known as "activation", is observed upon proinflammatory stimulation and leads astrocytes to acquire either a detrimental phenotype, thereby contributing to the neurodegenerative process, or a protective phenotype, thus supporting neuronal survival. Within the mechanisms responsible for inflammatory neurodegeneration, oxidative stress plays a major role and has recently been recognized to be heavily influenced by changes in cytosolic iron levels. In this work, we investigated how activation affects the competence of astrocytes to handle iron overload and the ensuing oxidative stress.Methods: Cultures of pure cortical astrocytes were preincubated with proinflammatory cytokines (interleukin-1Î2 and tumor necrosis factor α) or conditioned medium from lipopolysaccharide-activated microglia to promote activation and then exposed to a protocol of iron overload.Results: We demonstrate that activated astrocytes display an efficient protection against iron-mediated oxidative stress and cell death. Based on this evidence, we performed a comprehensive biochemical and molecular analysis, including a transcriptomic approach, to identify the molecular basis of this resistance.Conclusions: We propose the protective phenotype acquired after activation not to involve the most common astrocytic antioxidant pathway, based on the Nrf2 transcription factor, but to result from a complex change in the expression and activity of several genes involved in the control of cellular redox state
The Vimalakīrtinirdeśa Commentary [T1775] by Sengzhao et alii and the Chinese Conquest of Buddhism
No full textThis thesis undertakes an in-depth analysis of the Vimalakīrtinirdeśa Commentary (Zhu Weimojie jing 注維摩詰經 [T1775]), a collection of explanatory annotations on the Chinese version of the Vimalakīrtinirdeśa (406 AD) by the Kuchean translator Kumārajīva (344-413) and two of his Chinese “disciples”, namely Sengzhao 僧肇 (384-414) and Daosheng 道生 (ca 355-434). The text is analyzed and discussed from a number of different perspectives, each of those being articulated into one chapter and centered upon a specific concept. These are: 1. translation; 2. interpretation; 3. editing and transmission. The first chapter provides a “genealogy” of the Buddhist translation activity in the city of Chang’an, focusing on the work of three translators, viz. Dharmarakṣa, Dao’an 道安 and Kumārajīva. On the basis of this historical data I then analyze the Vimalakīrtinirdeśa Commentary as a typical “side-product” of Kumārajīva’s translation enterprise. The second chapter focuses on interpretation. It examines the three major commentaries included in Zhu Weimojie jing also in the light of the cultural background and the life trajectory of each author. Along with the content of the commentaries, my analysis puts a special emphasis on the modes of trans-cultural reception of Buddhist ideas, something which also entails a discussion of the “formal features” of each work. The third chapter focuses on the editing and transmission of the Vimalakīrtinirdeśa Commentary. Here I collect and discuss the most relevant available evidence regarding the textual history of the Commentary from its composition up to its first printing
UAUGs are responsible for low translational efficiency driven by BACE1 5′ UTR
No full text<p><b>Copyright information:</b></p><p>Taken from "Complex translational regulation of BACE1 involves upstream AUGs and stimulatory elements within the 5′ untranslated region"</p><p></p><p>Nucleic Acids Research 2007;35(9):2975-2985.</p><p>Published online 16 Apr 2007</p><p>PMCID:PMC1888809.</p><p>© 2007 The Author(s)</p> () Schematic representation of reporter mRNAs bearing mutations of uAUGs. Arrows represent uAUGs or UUGs when mutated; black boxes symbolize uORFs. () Transfection of reporter mRNAs into HeLa cell line. mRNA was used to normalize for transfection efficiency. Results are presented in fold variation, and the error bars present the mean of at least three independent experiments. Star indicates
Different regions of BACE1 5′ UTR affect translation in a positive or negative manner
No full text<p><b>Copyright information:</b></p><p>Taken from "Complex translational regulation of BACE1 involves upstream AUGs and stimulatory elements within the 5′ untranslated region"</p><p></p><p>Nucleic Acids Research 2007;35(9):2975-2985.</p><p>Published online 16 Apr 2007</p><p>PMCID:PMC1888809.</p><p>© 2007 The Author(s)</p> () Schematic representation of mRNAs bearing different BACE1 5′ UTR deletion mutants and firefly luciferase as reporter gene. Black boxes represent uORFs, and arrows uAUGs. () RNA transfections of different deletion mutants in HeLa cell line together with control reporter mRNA. The results are presented in fold variation. Error bars denote the standard deviation from the mean of at least three independent experiments. The star indicates
Inhibition of lipopolysaccharide-induced microglia activation by calcitonin gene related peptide and adrenomedullin
No full textIron uptake in quiescent and inflammation-activated astrocytes: A potentially neuroprotective control of iron burden
No full textAbstractAstrocytes play a crucial role in proper iron handling within the central nervous system. This competence can be fundamental, particularly during neuroinflammation, and neurodegenerative processes, where an increase in iron content can favor oxidative stress, thereby worsening disease progression. Under these pathological conditions, astrocytes undergo a process of activation that confers them either a beneficial or a detrimental role on neuronal survival. Our work investigates the mechanisms of iron entry in cultures of quiescent and activated hippocampal astrocytes. Our data confirm that the main source of iron is the non-transferrin-bound iron (NTBI) and show the involvement of two different routes for its entry: the resident transient receptor potential (TRP) channels in quiescent astrocytes and the de novo expressed divalent metal transporter 1 (DMT1) in activated astrocytes, which accounts for a potentiation of iron entry. Overall, our data suggest that at rest, but even more after activation, astrocytes have the potential to buffer the excess of iron, thereby protecting neurons from iron overload. These findings further extend our understanding of the protective role of astrocytes under the conditions of iron-mediated oxidative stress observed in several neurodegenerative conditions
VIP17/MAL, a proteolipid in apical transport vesicles
No full textAbstractVIP17 is a proteolipid enriched in the CHAPS-insoluble complexes from MDCK cells, and a candidate component of the molecular machinery responsible for the sorting and targeting of proteins to the apical surface. Cloning and sequencing of the cDNA encoding the protein revealed that it is the canine homolog of the human and rat MAL proteins. Analysis by immunofluorescence microscopy of epitope-tagged VIP17/MAL expressed transiently in BHK cells and stably in MDCK cells revealed a perinuclear, vesicular, and plasmalemmal staining. In MDCK cells the distribution was mainly in vesicular structures in the apical cytoplasm. These and other results suggest that VIP17/MAL is an important component in vesicular trafficking cycling between the Golgi complex and the apical plasma membrane
