The Experts below are selected from a list of 1572 Experts worldwide ranked by ideXlab platform
Thomas Deller - One of the best experts on this subject based on the ideXlab platform.
-
All-trans retinoic acid induces Synaptopodin-dependent metaplasticity in mouse dentate granule cells
'eLife Sciences Publications Ltd', 2021Co-Authors: Maximilian Lenz, Peter Jedlicka, Thomas Deller, Amelie Eichler, Pia Kruse, Julia Muellerleile, Andreas VlachosAbstract:Previously we showed that the vitamin A metabolite all-trans retinoic acid (atRA) induces synaptic plasticity in acute brain slices prepared from the mouse and human neocortex (Lenz et al., 2021). Depending on the brain region studied, distinct effects of atRA on excitatory and inhibitory neurotransmission have been reported. Here, we used intraperitoneal injections of atRA (10 mg/kg) in adult C57BL/6J mice to study the effects of atRA on excitatory and inhibitory neurotransmission in the mouse fascia dentata—a brain region implicated in memory acquisition. No major changes in synaptic transmission were observed in the ventral hippocampus while a significant increase in both spontaneous excitatory postsynaptic current frequencies and synapse numbers were evident in the dorsal hippocampus 6 hr after atRA administration. The intrinsic properties of hippocampal dentate granule cells were not significantly different and hippocampal transcriptome analysis revealed no essential neuronal changes upon atRA treatment. In light of these findings, we tested for the metaplastic effects of atRA, that is, for its ability to modulate synaptic plasticity expression in the absence of major changes in baseline synaptic strength. Indeed, in vivo long-term potentiation (LTP) experiments demonstrated that systemic atRA treatment improves the ability of dentate granule cells to express LTP. The plasticity-promoting effects of atRA were not observed in Synaptopodin-deficient mice, therefore, extending our previous results regarding the relevance of Synaptopodin in atRA-mediated synaptic strengthening in the mouse prefrontal cortex. Taken together, our data show that atRA mediates Synaptopodin-dependent metaplasticity in mouse dentate granule cells
-
structural plasticity of Synaptopodin in the axon initial segment during visual cortex development
Cerebral Cortex, 2017Co-Authors: Annabelle Schluter, Thomas Deller, Christian Schultz, Domenico Del Turco, Annika Gutzmann, Maren EngelhardtAbstract:The axon initial segment (AIS) is essential for action potential generation. Recently, the AIS was identified as a site of neuronal plasticity. A subpopulation of AIS in cortical principal neurons contains stacks of endoplasmic reticulum (ER) forming the cisternal organelle (CO). The function of this organelle is poorly understood, but roles in local Ca2+-trafficking and AIS plasticity are discussed. To investigate whether the presence and/or the size of COs are linked to the development and maturation of AIS of cortical neurons, we analyzed the relationship between COs and the AIS during visual cortex development under control and visual deprivation conditions. In wildtype mice, immunolabeling for Synaptopodin, ankyrin-G, and sIV-spectrin were employed to label COs and the AIS, respectively. Dark rearing resulted in an increase in Synaptopodin cluster sizes, suggesting a homeostatic function of the CO in this cellular compartment. In line with this observation, Synaptopodin-deficient mice lacking the CO showed AIS shortening in the dark. Collectively, these data demonstrate that the CO is an essential part of the AIS machinery required for AIS plasticity during a critical developmental period of the visual cortex.
-
impairment of in vivo theta burst long term potentiation and network excitability in the dentate gyrus of Synaptopodin deficient mice lacking the spine apparatus and the cisternal organelle
Hippocampus, 2009Co-Authors: Peter Jedlicka, Stephan W Schwarzacher, Carlos Bas Orth, Michael Frotscher, Raphael Winkels, Friederike Kienzler, Clive R Bramham, Christian Schultz, Thomas DellerAbstract:The function of the spine apparatus in dendritic spines and the cisternal organelles in axon initial segments is little understood. The actin-associated protein, Synaptopodin, is essential for the formation of these organelles which are absent in Synaptopodin 2/2 mice. Here, we used Synaptopodin 2/2 mice to explore the role of the spine appa- ratus and the cisternal organelle in synaptic plasticity and local circuit excitability in response to activation of the perforant path input to the dentate gyrus in vivo. We found impaired long-term potentiation follow- ing theta-burst stimulation, whereas tetanus-evoked LTP was unaffected. Furthermore, paired-pulse inhibition of the population spike was reduced and granule cell excitability was enhanced in mutants, hence revealing an impairment of local network inhibition. In summary, our data represent the first electrophysiological evidence that the lack of the spine apparatus and the cisternal organelle leads to a defect in long- term synaptic plasticity and alterations in local circuit control of granule cell excitability under adult in vivo conditions. V C 2008 Wiley-Liss, Inc.
-
a role for the spine apparatus in ltp and spatial learning
Behavioural Brain Research, 2008Co-Authors: Peter Jedlicka, Andreas Vlachos, Stephan W Schwarzacher, Thomas DellerAbstract:Long-term potentiation (LTP) of synaptic strength is a long-lasting form of synaptic plasticity that has been linked to information storage. Although the molecular and cellular events underlying LTP are not yet fully understood, it is generally accepted that changes in dendritic spine calcium levels as well as local protein synthesis play a central role. These two processes may be influenced by the presence of a spine apparatus, a distinct neuronal organelle found in a subpopulation of telencephalic spines. Mice lacking spine apparatuses (Synaptopodin-deficient mice) show deficits in LTP and impaired spatial learning supporting the involvement of the spine apparatus in synaptic plasticity. In our review, we consider the possible roles of the spine apparatus in LTP1 (protein synthesis-independent), LTP2 (translation-dependent and transcription-independent) and LTP3 (translation- and transcription-dependent) and discuss the effects of the spine apparatus on learning and memory.
-
a role for Synaptopodin and the spine apparatus in hippocampal synaptic plasticity
Annals of Anatomy-anatomischer Anzeiger, 2007Co-Authors: Thomas Deller, Andreas Vlachos, Martin Korte, Sophie Chabanis, Alexander Drakew, Herbert Schwegler, Carlos Bas Orth, Domenico Del Turco, Guido J Burbach, Carola A HaasAbstract:Spines are considered sites of synaptic plasticity in the brain and are capable of remodeling their shape and size. A molecule thathas been implicated in spine plasticity is the actin-associated protein Synaptopodin. This article will review a series of studies aimed at elucidating the role of Synaptopodin in the rodent brain. First, the developmental expression of Synaptopodin mRNA and protein were studied; secondly, the subcellular localization of Synaptopodin in hippocampal principal neurons was analyzed using confocal microscopy as well as electron microscopy and immunogold labelling; and, finally, the functional role of Synaptopodin was investigated using a Synaptopodin-deficient mouse. The results of these studies are: (1) Synaptopodin expression byhippocampal principal neurons develops during the first postnatal weeks and increases in parallel with the maturation of spines in the hippocampus. (2) Synaptopodin is sorted to the spine compartment, where it is tightly associated with the spine apparatus, an enigmatic organelle believed to be involved in calcium storage or local protein synthesis. (3) Synaptopodin-deficient mice generated by gene targeting are viable but lack the spine apparatus organelle. These mice show deficitsin synaptic plasticity as well as impaired learning and memory. Taken together, these data implicate Synaptopodin and the spine apparatus in the regulation of synaptic plasticity in the hippocampus. Future studies will be aimed at finding the molecular link between Synaptopodin, the spine apparatus organelle, and synaptic plasticity.
Peter Mundel - One of the best experts on this subject based on the ideXlab platform.
-
Synaptopodin is a coincidence detector of tyrosine versus serine threonine phosphorylation for the modulation of rho protein crosstalk in podocytes
Journal of The American Society of Nephrology, 2017Co-Authors: Lisa Buvall, Hanna Wallentin, Jonas Sieber, Svetlana Andreeva, Hoon Young Choi, Peter Mundel, Anna GrekaAbstract:Tyrosine and serine/threonine signal-transduction pathways influence many aspects of cell behavior, including the spatial and temporal regulation of the actin cytoskeleton. However, little is known about how input from diverse tyrosine and serine/threonine kinases is integrated to control Rho protein crosstalk and actin remodeling, which are critically important in podocyte health and disease. Here we unveil the proteolytically-regulated, actin organizing protein Synaptopodin as a coincidence detector of tyrosine versus serine/threonine phosphorylation. We show that serine/threonine and tyrosine kinases duel for Synaptopodin stability versus degradation. EGFR/Src-mediated tyrosine phosphorylation of Synaptopodin in podocytes promotes binding to the serine/threonine phosphatase calcineurin. This leads to the loss of 14–3-3 binding, resulting in Synaptopodin degradation, Vav2 activation, enhanced Rac1 signaling, and ultimate loss of stress fibers. Our studies reveal how Synaptopodin, a single proteolytically-controlled protein, integrates antagonistic tyrosine versus serine/threonine phosphorylation events for the dynamic control of the actin cytoskeleton in podocytes.
-
Rescue of tropomyosin deficiency in Drosophila
2016Co-Authors: Michelle N Rheault, Christian Faul, Toby M Ward, Priyanka Rashmi, Ursula Weber, Marek Mlodzik, Peter MundelAbstract:and human cancer cells by Synaptopodin reveals a role of tropomyosin a in RhoA stabilizatio
-
essential role for Synaptopodin in dendritic spine plasticity of the developing hippocampus
The Journal of Neuroscience, 2013Co-Authors: Xiaolei Zhang, Beatrice Poschel, Christian Faul, Chirag Upreti, Patric K Stanton, Peter MundelAbstract:Dendritic spines are a major substrate of brain plasticity. Although many studies have focused on Ca2+/calmodulin-dependent protein kinase II (CaMKII)-mediated regulation of spine dynamics and synaptic function in adult brain, much less is know about protein kinase A (PKA)-dependent regulation of spine shape dynamics during postnatal brain development. Synaptopodin is a dendritic spine associated modulator of actin dynamics and a substrate of PKA. Here we show that NMDA and cAMP-induced dendritic spine expansion is impaired in hippocampal slices from 15- and 21-d-old Synaptopodin-deficient mice. We further show that Synaptopodin is required for full expression of PKA-dependent hippocampal long-term potentiation in 15- and 21-d-old, but not adult, mice. PKA-induced cAMP response element-binding phosphorylation is normal in the hippocampus of Synaptopodin-deficient mice, suggesting that Synaptopodin functions independently of cAMP response element-binding. Our results identify Synaptopodin as a substrate of PKA in hippocampal neurons and point to an essential role for Synaptopodin in activity-dependent regulation of dendritic spine dynamics and synaptic plasticity in postnatal brain development.
-
rescue of tropomyosin deficiency in drosophila and human cancer cells by Synaptopodin reveals a role of tropomyosin α in rhoa stabilization
The EMBO Journal, 2012Co-Authors: Jenny Wong, Christian Faul, Elizabeth Iorns, Michelle N Rheault, Toby M Ward, Priyanka Rashmi, Ursula Weber, Marc E Lippman, Marek Mlodzik, Peter MundelAbstract:Tropomyosins are widespread actin-binding proteins that influence numerous cellular functions including actin dynamics, cell migration, tumour suppression, and Drosophila oocyte development. Synaptopodin is another actin-binding protein with a more restricted expression pattern in highly dynamic cell compartments such as kidney podocyte foot processes, where it promotes RhoA signalling by blocking the Smurf1-mediated ubiquitination of RhoA. Here, we show that Synaptopodin has a shorter half-life but shares functional properties with the highly stable tropomyosin. Transgenic expression of Synaptopodin restores oskar mRNA localization in Drosophila oocytes mutant for TmII, thereby rescuing germline differentiation and fertility. Synaptopodin restores stress fibres in tropomyosin-deficient human MDA-MB 231 breast cancer cells and TPMα-depleted fibroblasts. Gene silencing of TPMα but not TPMβ causes loss of stress fibres by promoting Smurf1-mediated ubiquitination and proteasomal degradation of RhoA. Functionally, overexpression of Synaptopodin or RhoA(K6,7R) significantly reduces MDA-MB 231 cell migration. Our findings elucidate RhoA stabilization by structurally unrelated actin-binding proteins as a conserved mechanism for regulation of stress fibre dynamics and cell motility in a cell type-specific fashion.
-
Synaptopodin orchestrates actin organization and cell motility via regulation of rhoa signalling
Nature Cell Biology, 2006Co-Authors: Katsuhiko Asanuma, Christian Faul, Kwanghee Kim, Etsuko Yanagidaasanuma, Yasuhiko Tomino, Peter MundelAbstract:The Rho family of small GTPases (RhoA, Rac1 and Cdc42) controls signal-transduction pathways that influence many aspects of cell behaviour, including cytoskeletal dynamics. At the leading edge, Rac1 and Cdc42 promote cell motility through the formation of lamellipodia and filopodia, respectively. On the contrary, RhoA promotes the formation of contractile actin-myosin-containing stress fibres in the cell body and at the rear. Here, we identify Synaptopodin, an actin-associated protein, as a novel regulator of RhoA signalling and cell migration in kidney podocytes. We show that Synaptopodin induces stress fibres by competitive blocking of Smurf1-mediated ubiquitination of RhoA, thereby preventing the targeting of RhoA for proteasomal degradation. Gene silencing of Synaptopodin in kidney podocytes causes the loss of stress fibres and the formation of aberrant non-polarized filopodia and impairment of cell migration. Together, these data show that Synaptopodin is essential for the integrity of the podocyte actin cytoskeleton and for the regulation of podocyte cell migration.
Gail Vw Johnson - One of the best experts on this subject based on the ideXlab platform.
-
bag3 and synpo Synaptopodin facilitate phospho mapt tau degradation via autophagy in neuronal processes
Autophagy, 2019Co-Authors: Changyi Ji, Maoping Tang, Claudia Zeidler, Jörg Höhfeld, Gail Vw JohnsonAbstract:ABSTRACTA major cellular catabolic pathway in neurons is macroautophagy/autophagy, through which misfolded or aggregation-prone proteins are sequestered into autophagosomes that fuse with lysosomes...
-
bag3 and synpo Synaptopodin facilitate phospho mapt tau degradation via autophagy in neuronal processes
bioRxiv, 2019Co-Authors: Maoping Tang, Claudia Zeidler, Jörg Höhfeld, Gail Vw JohnsonAbstract:A major cellular catabolic pathway in neurons is macroautophagy/autophagy, through which misfolded or aggregation-prone proteins are sequestered into autophagosomes that fuse with lysosomes, and are subsequently degraded. MAPT (microtubule associated protein tau) is one of the protein clients of autophagy. Given that accumulation of hyperphosphorylated MAPT contributes to the pathogenesis of Alzheimer disease and other tauopathies, decreasing endogenous MAPT levels has been shown to be beneficial to neuronal health in models of these diseases. A previous study demonstrated that the HSPA/HSP70 co-chaperone BAG3 (BCL2 associated athanogene 3) facilitates endogenous MAPT clearance through autophagy. These findings prompted us to further investigate the mechanisms underlying BAG3-mediated autophagy in the degradation of endogenous MAPT. Here we demonstrate for the first time that BAG3 plays an important role in autophagic flux in the neuritic processes of mature neurons (20-24 days in vitro [DIV]) through interaction with the post-synaptic cytoskeleton protein SYNPO (Synaptopodin). Loss of either BAG3 or SYNPO impeded the fusion of autophagosomes and lysosomes predominantly in the post-synaptic compartment. A block of autophagy leads to accumulation of the autophagic receptor protein SQSTM1/p62 (sequestosome 1) as well as MAPT phosphorylated at Ser262 (p-Ser262). Furthermore, p-Ser262 appears to accumulate in autophagosomes at post-synaptic densities. Overall these data provide evidence of a novel role for the co-chaperone BAG3 in synapses. In cooperation with SYNPO, it functions as part of a surveillance complex that facilitates the autophagic clearance of MAPT p-Ser262, and possibly other MAPT species at the post-synapse. This appears to be crucial for the maintenance of a healthy, functional synapse.
-
BAG3 and SYNPO (Synaptopodin) facilitate phospho-MAPT/Tau degradation via autophagy in neuronal processes
2019Co-Authors: Maoping Tang, Claudia Zeidler, Jörg Höhfeld, Gail Vw JohnsonAbstract:A major cellular catabolic pathway in neurons is macroautophagy/autophagy, through which misfolded or aggregation-prone proteins are sequestered into autophagosomes that fuse with lysosomes, and are degraded. MAPT (microtubule-associated protein tau) is one of the protein clients of autophagy. Given that accumulation of hyperphosphorylated MAPT contributes to the pathogenesis of Alzheimer disease and other tauopathies, decreasing endogenous MAPT levels has been shown to be beneficial to neuronal health in models of these diseases. A previous study demonstrated that the HSPA/HSP70 co-chaperone BAG3 (BCL2-associated athanogene 3) facilitates endogenous MAPT clearance through autophagy. These findings prompted us to further investigate the mechanisms underlying BAG3-mediated autophagy in the degradation of endogenous MAPT. Here we demonstrate for the first time that BAG3 plays an important role in autophagic flux in the neurites of mature neurons (20–24 days in vitro [DIV]) through interaction with the post-synaptic cytoskeleton protein SYNPO (Synaptopodin). Loss of either BAG3 or SYNPO impeded the fusion of autophagosomes and lysosomes predominantly in the post-synaptic compartment. A block of autophagy leads to accumulation of the autophagic receptor protein SQSTM1/p62 (sequestosome 1) as well as MAPT phosphorylated at Ser262 (p-Ser262). Furthermore, p-Ser262 appears to accumulate in autophagosomes at post-synaptic densities. Overall these data provide evidence of a novel role for the co-chaperone BAG3 in synapses. In cooperation with SYNPO, it functions as part of a surveillance complex that facilitates the autophagic clearance of MAPT p-Ser262, and possibly other MAPT species at the post-synapse. This appears to be crucial for the maintenance of a healthy, functional synapse.Abbreviations: aa: amino acids; ACTB: actin beta; BafA1: bafilomycin A1; BAG3: BCL2 associated athanogene 3; CQ chloroquine; CTSL: cathepsin L; DIV: days in vitro; DLG4/PSD95: discs large MAGUK scaffold protein 4; HSPA/HSP70: heat shock protein family A (Hsp70); MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAP2: microtubule associated protein 2; MAPT: microtubule associated protein tau; p-Ser262: MAPT phosphorylated at serine 262; p-Ser396/404: MAPT phosphorylated at serines 396 and 404; p-Thr231: MAPT phosphorylated at threonine 231; PBS: phosphate buffered saline; PK: proteinase K; scr: scrambled; shRNA: short hairpin RNA; SQSTM1/p62 sequestosome 1; SYN1: synapsin I; SYNPO Synaptopodin; SYNPO2/myopodin: Synaptopodin 2; VPS: vacuolar protein sorting
Alberto Muñoz - One of the best experts on this subject based on the ideXlab platform.
-
colocalization of α actinin and Synaptopodin in the pyramidal cell axon initial segment
Cerebral Cortex, 2012Co-Authors: Lidia Blazquezllorca, Diana Sanchezponce, Juan José Garrido, Alberto Muñoz, Javier DefelipeAbstract:The cisternal organelle that resides in the axon initial segment (AIS) of neocortical and hippocampal pyramidal cells is thought to be involved in regulating the Ca(2+) available to maintain AIS scaffolding proteins, thereby preserving normal AIS structure and function. Through immunocytochemistry and correlative light and electron microscopy, we show here that the actin-binding protein ?-actinin is present in the typical cistenal organelle of rodent pyramidal neurons as well as in a large structure in the AIS of a subpopulation of layer V pyramidal cells that we have called the "giant saccular organelle." Indeed, this localization of ?-actinin in the AIS is dependent on the integrity of the actin cytoskeleton. Moreover, in the cisternal organelle of cultured hippocampal neurons, ?-actinin colocalizes extensively with Synaptopodin, a protein that interacts with both actin and ?-actinin, and they appear concomitantly during the development of these neurons. Together, these results indicate that ?-actinin and the actin cytoskeleton are important components of the cisternal organelle that are probably required to stabilize the AIS.
Diana Sanchezponce - One of the best experts on this subject based on the ideXlab platform.
-
colocalization of α actinin and Synaptopodin in the pyramidal cell axon initial segment
Cerebral Cortex, 2012Co-Authors: Lidia Blazquezllorca, Diana Sanchezponce, Juan José Garrido, Alberto Muñoz, Javier DefelipeAbstract:The cisternal organelle that resides in the axon initial segment (AIS) of neocortical and hippocampal pyramidal cells is thought to be involved in regulating the Ca(2+) available to maintain AIS scaffolding proteins, thereby preserving normal AIS structure and function. Through immunocytochemistry and correlative light and electron microscopy, we show here that the actin-binding protein ?-actinin is present in the typical cistenal organelle of rodent pyramidal neurons as well as in a large structure in the AIS of a subpopulation of layer V pyramidal cells that we have called the "giant saccular organelle." Indeed, this localization of ?-actinin in the AIS is dependent on the integrity of the actin cytoskeleton. Moreover, in the cisternal organelle of cultured hippocampal neurons, ?-actinin colocalizes extensively with Synaptopodin, a protein that interacts with both actin and ?-actinin, and they appear concomitantly during the development of these neurons. Together, these results indicate that ?-actinin and the actin cytoskeleton are important components of the cisternal organelle that are probably required to stabilize the AIS.
