Elena Tortosa - Academia.edu (original) (raw)

Papers by Elena Tortosa

Research paper thumbnail of Stress‐induced vesicular assemblies of dual leucine zipper kinase are signaling hubs involved in kinase activation and neurodegeneration

Research paper thumbnail of DynamicsandBiotechnology,FacultyofSciences,UniversidaddeChile,LasPalmeras3425,Ñuñoa,Santiago,Chile,the LaboratoryforScientificImageAnalysis(SCIAN-Lab)attheAnatomyandDevelopmentalBiologyProgram,ICBM,Universidadde

Research paper thumbnail of Binding of Hsp90 to tau promotes a conformational change and aggregation of tau protein

Journal of Alzheimer's disease : JAD, 2009

Tau pathology, associated with Alzheimer's disease, is characterized by the presence of phosp... more Tau pathology, associated with Alzheimer's disease, is characterized by the presence of phosphorylated and aggregated tau. Phosphorylation of tau takes place mainly in the vicinity of the tubulin-binding region of the molecule and its self aggregation is also mediated via this tubulin-binding region. Tau phosphorylation and aggregation have been related with conformational changes of the protein. These changes could be regulated by chaperones such as heat shock proteins, since one of these, heat shock protein 90 (Hsp90), has already been described as a putative tau-binding protein. In this work, we have confirmed the interaction of Hsp90 with tau protein and report that binding of Hsp90 to tau facilitates a conformational change that could result in its phosphorylation by glycogen synthase kinase 3 and its aggregation into filamentous structures.

Research paper thumbnail of The Kinesin-2 Family Member KIF3C Regulates Microtubule Dynamics and Is Required for Axon Growth and Regeneration

Journal of Neuroscience, 2013

Axon regeneration after injury requires the extensive reconstruction, reorganization, and stabili... more Axon regeneration after injury requires the extensive reconstruction, reorganization, and stabilization of the microtubule cytoskeleton in the growth cones. Here, we identify KIF3C as a key regulator of axonal growth and regeneration by controlling microtubule dynamics and organization in the growth cone. KIF3C is developmentally regulated. Rat embryonic sensory axons and growth cones contain undetectable levels of KIF3C protein that is locally translated immediately after injury. In adult neurons, KIF3C is axonally transported from the cell body and is enriched at the growth cone where it preferentially binds to tyrosinated microtubules. Functionally, the interaction of KIF3C with EB3 is necessary for its localization at the microtubule plus-ends in the growth cone. Depletion of KIF3C in adult neurons leads to an increase in stable, overgrown and looped microtubules because of a strong decrease in the microtubule frequency of catastrophes, suggesting that KIF3C functions as a microtubule-destabilizing factor. Adult axons lacking KIF3C, by RNA interference or KIF3C gene knockout , display an impaired axonal outgrowth in vitro and a delayed regeneration after injury both in vitro and in vivo. Murine KIF3C knockout embryonic axons grow normally but do not regenerate after injury because they are unable to locally translate KIF3C. These data show that KIF3C is an injury-specific kinesin that contributes to axon growth and regeneration by regulating and organizing the microtubule cytoskeleton in the growth cone.

Research paper thumbnail of MAP1B-dependent Rac activation is required for AMPA receptor endocytosis during long-term depression

The EMBO Journal, 2013

The microtubule-associated protein 1B (MAP1B) plays critical roles in neurite growth and synapse ... more The microtubule-associated protein 1B (MAP1B) plays critical roles in neurite growth and synapse maturation during brain development. This protein is well expressed in the adult brain. However, its function in mature neurons remains unknown. We have used a genetically modified mouse model and shRNA techniques to assess the role of MAP1B at established synapses, bypassing MAP1B functions during neuronal development. Under these conditions, we found that MAP1B deficiency alters synaptic plasticity by specifically impairing long-term depression (LTD) expression. Interestingly, this is due to a failure to trigger AMPA receptor endocytosis and spine shrinkage during LTD. These defects are accompanied by an impaired targeting of the Rac1 activator Tiam1 at synaptic compartments. Accordingly, LTD and AMPA receptor endocytosis are restored in MAP1B-deficient neurons by providing additional Rac1. Therefore, these results indicate that the MAP1B-Tiam1-Rac1 relay is essential for spine structural plasticity and removal of AMPA receptors from synapses during LTD. This work highlights the importance of MAPs as signalling hubs controlling the actin cytoskeleton and receptor trafficking during plasticity in mature neurons.

Research paper thumbnail of MAP1B binds to the NMDA receptor subunit NR3A and affects NR3A protein concentrations

Neuroscience Letters, 2010

Incorporation of the N-methyl-d-aspartate receptor (NMDAR) subunit NR3A into functional NMDARs re... more Incorporation of the N-methyl-d-aspartate receptor (NMDAR) subunit NR3A into functional NMDARs results in reduced channel conductance and Ca(2+) permeability. To further investigate the function of NR3A, we have set out to characterize its intracellular binding partners. Here, we report a novel protein interaction between NR3A and microtubule associated-protein (MAP) 1B, which both are localized to dendritic shafts and filopodia. NR3A protein levels were increased in MAP1B deficient (-/-) mice, with a corresponding decrease in NR1 levels, but the fraction of filopodia immunoreactive for NR3A was equal in cells from -/- and wild type (WT) mice. NR3A has previously been shown to interact with another member of the MAP1 family, MAP1S. We showed that MAP1S binds to microtubules in a similar manner as MAP1B, and suggest that MAP1S and MAP1B both are involved in regulating trafficking of NR3A-containing NMDAR.

Research paper thumbnail of MAP1B Regulates Axonal Development by Modulating Rho-GTPase Rac1 Activity

Molecular Biology of the Cell, 2010

Cultured neurons obtained from MAP1B-deficient mice have a delay in axon outgrowth and a reduced ... more Cultured neurons obtained from MAP1B-deficient mice have a delay in axon outgrowth and a reduced rate of axonal elongation compared with neurons from wild-type mice. Here we show that MAP1B deficiency results in a significant decrease in Rac1 and cdc42 activity and a significant increase in Rho activity. We found that MAP1B interacted with Tiam1, a guanosine nucleotide exchange factor for Rac1. The decrease in Rac1/cdc42 activity was paralleled by decreases in the phosphorylation of the downstream effectors of these proteins, such as LIMK-1 and cofilin. The expression of a constitutively active form of Rac1, cdc42, or Tiam1 rescued the axon growth defect of MAP1B-deficient neurons. Taken together, these observations define a new and crucial function of MAP1B that we show to be required for efficient cross-talk between microtubules and the actin cytoskeleton during neuronal polarization.

Research paper thumbnail of Microtubule-associated Protein 1B (MAP1B) Is Required for Dendritic Spine Development and Synaptic Maturation

Journal of Biological Chemistry, 2011

Background: Microtubule-associated protein 1B (MAP1B) is a protein that is prominently expressed ... more Background: Microtubule-associated protein 1B (MAP1B) is a protein that is prominently expressed during early neuronal development but in adult brain remains in areas with high synaptic plasticity. Results: MAP1B plays an important role in dendritic spine formation and synaptic maturation. Conclusion: A novel function for MAP1B in regulating dendritic spine morphology and synaptic function is indicated. Significance: MAP1B could contribute to adult brain plasticity.

Research paper thumbnail of Microtubule-Associated Protein 1B Interaction with Tubulin Tyrosine Ligase Contributes to the Control of Microtubule Tyrosination

Developmental Neuroscience, 2007

Research paper thumbnail of The role of the VQIVYK peptide in tau protein phosphorylation

Journal of Neurochemistry, 2007

Although it remains unclear whether they are related to one another, tau aggregation and phosphor... more Although it remains unclear whether they are related to one another, tau aggregation and phosphorylation are the main pathological hallmarks of the neuronal disorders known as tauopathies. The capacity to aggregate is impaired in a variant of the tau 3R isoform that lacks residues 306-311 (nomenclature for the largest CNS tau isoform) and hence, we have taken advantage of this feature to study how phosphorylation and aggregation may be related as well as the role of this six amino acid peptide (VQIVYK). Through these analyses, we found that the phosphorylation of the tau variant was higher than that of the complete tau protein and that not only the deletion of these residues, but also the interaction of these residues, in tau 3R, with thioflavin-S augmented tau phosphorylation by glycogen synthase kinase 3. In addition, the binding of the peptide containing the residues 306-311 to the whole tau protein provoked an increase in tau phosphorylation. This observation could be physiologically relevant as may suggest that tau-tau interactions, through those residues, facilitate tau phosphorylation. In summary, our data indicate that deletion of residues VQIVYK, in tau protein produces an increase in tau phosphorylation, without tau aggregation, because the VQIVYK peptide, that favors aggregation, is missing. On the other hand, when the whole tau protein interacts with thioflavin-S or the peptide VQIVYK, an increase in both aggregation and phosphorylation occurs.

Research paper thumbnail of Role of MAP1B in hipocampal synaptic plasticity

Research paper thumbnail of Polarized trafficking: the palmitoylation cycle distributes cytoplasmic proteins to distinct neuronal compartments

Current Opinion in Cell Biology

In neurons, polarized cargo distribution occurs mainly between the soma and axonal and dendritic ... more In neurons, polarized cargo distribution occurs mainly between the soma and axonal and dendritic compartments, and requires coordinated regulation of cytoskeletal remodeling and membrane trafficking. The Golgi complex plays a critical role during neuronal polarization and secretory trafficking has been shown to differentially transport proteins to both axons and dendrites. Besides the Golgi protein sorting, recent data revealed that palmitoylation cycles are an efficient mechanism to localize cytoplasmic, non-transmembrane proteins to particular neuronal compartments, such as the newly formed axon. Palmitoylation allows substrate proteins to bind to and ride with Golgi-derived secretory vesicles to all neuronal compartments. By allowing cytoplasmic proteins to 'hitchhike' on transport carriers in a non-polarized fashion, compartmentalized depalmitoylation may act as a selective retention mechanism.

Research paper thumbnail of Feedback-Driven Mechanisms between Microtubules and the Endoplasmic Reticulum Instruct Neuronal Polarity

Neuron

Highlights d ER tubules localize to the axon, and ER cisternae are retained in the soma d Localiz... more Highlights d ER tubules localize to the axon, and ER cisternae are retained in the soma d Localization of axonal ER depends on ER-shaping proteins and the MT cytoskeleton d ER-MT crosstalk stabilizes both ER tubules and MTs in the axon d ER-MT crosstalk is critical for neuronal polarity

Research paper thumbnail of Microtubule Organization and Microtubule-Associated Proteins (MAPs)

Dendrites, 2016

Dendrites have a unique microtubule organization. In vertebrates, dendritic microtubules are orga... more Dendrites have a unique microtubule organization. In vertebrates, dendritic microtubules are organized in antiparallel bundles, oriented with their plus ends either pointing away or toward the soma. The mixed microtubule arrays control intracellular trafficking and local signaling pathways, and are essential for dendrite development and function. The organization of microtubule arrays largely depends on the combined function of different microtubule regulatory factors or generally named microtubule-associated proteins (MAPs). Classical MAPs, also called structural MAPs, were identified more than 20 years ago based on their ability to bind to and copurify with microtubules. Most classical MAPs bind along the microtubule lattice and regulate microtubule polymerization, bundling, and stabilization. Recent evidences suggest that classical MAPs also guide motor protein transport, interact with the actin cytoskeleton, and act in various neuronal signaling networks. Here, we give an overview of microtubule organization in dendrites and the role of classical MAPs in dendrite development, dendritic spine formation, and synaptic plasticity.

Research paper thumbnail of Three-Step Model for Polarized Sorting of KIF17 into Dendrites

Current Biology, 2016

Highlights d Cargo binding relieves autoinhibition of KIF17 in living cells d KIF17-bound cargo d... more Highlights d Cargo binding relieves autoinhibition of KIF17 in living cells d KIF17-bound cargo does not autonomously target dendrites d KIF17-bound cargoes enter the axon but anchor at the AIS d Dynein redirects KIF17-bound cargo into dendrites

Research paper thumbnail of Dendrites In Vitro and In Vivo Contain Microtubules of Opposite Polarity and Axon Formation Correlates with Uniform Plus-End-Out Microtubule Orientation

Journal of Neuroscience, 2016

In cultured vertebrate neurons, axons have a uniform arrangement of microtubules with plus-ends d... more In cultured vertebrate neurons, axons have a uniform arrangement of microtubules with plus-ends distal to the cell body (plus-end-out), whereas dendrites contain mixed polarity orientations with both plus-end-out and minus-end-out oriented microtubules. Rather than non-uniform microtubules, uniparallel minus-end-out microtubules are the signature of dendrites in Drosophila and Caenorhabditis elegans neurons. To determine whether mixed microtubule organization is a conserved feature of vertebrate dendrites, we used live-cell imaging to systematically analyze microtubule plus-end orientations in primary cultures of rat hippocampal and cortical neurons, dentate granule cells in mouse organotypic slices, and layer 2/3 pyramidal neurons in the somatosensory cortex of living mice. In vitro and in vivo, all microtubules had a plus-end-out orientation in axons, whereas microtubules in dendrites had mixed orientations. When dendritic microtubules were severed by laser-based microsurgery, we detected equal numbers of plus-and minus-end-out microtubule orientations throughout the dendritic processes. In dendrites, the minus-end-out microtubules were generally more stable and comparable with plus-end-out microtubules in axons. Interestingly, at early stages of neuronal development in nonpolarized cells, newly formed neurites already contained microtubules of opposite polarity, suggesting that the establishment of uniform plus-end-out microtubules occurs during axon formation. We propose a model in which the selective formation of uniform plus-end-out microtubules in the axon is a critical process underlying neuronal polarization.

Research paper thumbnail of Tau regulates the localization and function of End Binding proteins in neuronal cells

SpringerPlus, 2015

MicroRNAs (miRNAs) are short, 22-25 nucleotide long transcripts that may suppress entire signalin... more MicroRNAs (miRNAs) are short, 22-25 nucleotide long transcripts that may suppress entire signaling pathways by interacting with the 3'-untranslated region (3'-UTR) of coding mRNA targets, interrupting translation and inducing degradation of these targets. The long 3'-UTRs of brain transcripts compared to other tissues predict important roles for brain miRNAs. Supporting this notion, we found that brain miRNAs co-evolved with their target transcripts, that non-coding pseudogenes with miRNA recognition elements compete with brain coding mRNAs on their miRNA interactions, and that Single Nucleotide Polymorphisms (SNPs) on such pseudogenes are enriched in mental diseases including autism and schizophrenia, but not Alzheimer's disease (AD). Focusing on evolutionarily conserved and primate-specifi c miRNA controllers of cholinergic signaling ('CholinomiRs'), we fi nd modifi ed CholinomiR levels in the brain and/or nucleated blood cells of patients with AD and Parkinson's disease, with treatment-related diff erences in their levels and prominent impact on the cognitive and anti-infl ammatory consequences of cholinergic signals. Examples include the acetylcholinesterase (AChE)-targeted evolutionarily conserved miR-132, whose levels decline drastically in the AD brain. Furthermore, we found that interruption of AChE mRNA's interaction with the primatespecifi c CholinomiR-608 in carriers of a SNP in the AChE's miR-608 binding site induces domino-like eff ects that reduce the levels of many other miR-608 targets. Young, healthy carriers of this SNP express 40% higher brain AChE activity than others, potentially aff ecting the responsiveness to AD's anti-AChE therapeutics, and show elevated trait anxiety, infl ammation and hypertension. Non-coding regions aff ecting miRNA-target interactions in neurodegenerative brains thus merit special attention.

Research paper thumbnail of Tau regulates the localization and function of End-binding proteins 1 and 3 (EB1/3) in developing neuronal cells

Journal of neurochemistry, Jan 11, 2015

The axonal microtubule-associated protein (MAP) tau is a well-known regulator of microtubule stab... more The axonal microtubule-associated protein (MAP) tau is a well-known regulator of microtubule stability in neurons. However, the putative interplay between tau and End-binding proteins 1 and 3 (EB1/3), the core microtubule plus-end tracking proteins (+TIPs), has not been elucidated yet. Here we show that a crosstalk between tau and EB1/3 exists in developing neuronal cells. Tau and EBs partially colocalize at extending neurites of N1E-115 neuroblastoma cells and axons of primary hippocampal neurons, as shown by confocal immunofluorescence analyses. Tau downregulation leads to a reduction of EB1/3 comet length, as observed in shRNA-stably depleted neuroblastoma cells and TAU-/- neurons. EB1/3 localization depends on the expression levels and localization of tau protein. Overexpression of tau at high levels induces EBs relocalization to microtubule bundles at extending neurites of N1E-115 cells. In differentiating primary neurons, tau is required for the proper accumulation of EBs at s...

Research paper thumbnail of MAP1B regulates microtubule dynamics by sequestering EB1/3 in the cytosol of developing neuronal cells

The EMBO Journal, 2013

MAP1B, a structural microtubule (MT)-associated protein highly expressed in developing neurons, p... more MAP1B, a structural microtubule (MT)-associated protein highly expressed in developing neurons, plays a key role in neurite and axon extension. However, not all molecular mechanisms by which MAP1B controls MT dynamics during these processes have been revealed. Here, we show that MAP1B interacts directly with EB1 and EB3 (EBs), two core 'microtubule plus-end tracking proteins' (+TIPs), and sequesters them in the cytosol of developing neuronal cells. MAP1B overexpression reduces EBs binding to plus-ends, whereas MAP1B downregulation increases binding of EBs to MTs. These alterations in EBs behaviour lead to changes in MT dynamics, in particular overstabilization and looping, in growth cones of MAP1B-deficient neurons. This contributes to growth cone remodelling and a delay in axon outgrowth. Together, our findings define a new and crucial role of MAP1B as a direct regulator of EBs function and MT dynamics during neurite and axon extension. Our data provide a new layer of MT regulation: a classical MAP, which binds to the MT lattice and not to the end, controls effective concentration of core +TIPs thereby regulating MTs at their plus-ends.

Research paper thumbnail of Acetylsalicylic acid decreases tau phosphorylation at serine 422

Neuroscience Letters, 2006

Tau protein pathology in Alzheimer's disease is characterized by the hyperphosphorylation of tau ... more Tau protein pathology in Alzheimer's disease is characterized by the hyperphosphorylation of tau at some specific sites. One of these sites is serine 422 which modification has been correlated with a possible toxic effect of phosphotau in neural cells. In this work, we have found that in the presence of acetylsalicylic acid, at a concentration like that used for anti-inflammatory treatments, tau phosphorylation at serine 422 decreases.

Research paper thumbnail of Stress‐induced vesicular assemblies of dual leucine zipper kinase are signaling hubs involved in kinase activation and neurodegeneration

Research paper thumbnail of DynamicsandBiotechnology,FacultyofSciences,UniversidaddeChile,LasPalmeras3425,Ñuñoa,Santiago,Chile,the LaboratoryforScientificImageAnalysis(SCIAN-Lab)attheAnatomyandDevelopmentalBiologyProgram,ICBM,Universidadde

Research paper thumbnail of Binding of Hsp90 to tau promotes a conformational change and aggregation of tau protein

Journal of Alzheimer's disease : JAD, 2009

Tau pathology, associated with Alzheimer's disease, is characterized by the presence of phosp... more Tau pathology, associated with Alzheimer's disease, is characterized by the presence of phosphorylated and aggregated tau. Phosphorylation of tau takes place mainly in the vicinity of the tubulin-binding region of the molecule and its self aggregation is also mediated via this tubulin-binding region. Tau phosphorylation and aggregation have been related with conformational changes of the protein. These changes could be regulated by chaperones such as heat shock proteins, since one of these, heat shock protein 90 (Hsp90), has already been described as a putative tau-binding protein. In this work, we have confirmed the interaction of Hsp90 with tau protein and report that binding of Hsp90 to tau facilitates a conformational change that could result in its phosphorylation by glycogen synthase kinase 3 and its aggregation into filamentous structures.

Research paper thumbnail of The Kinesin-2 Family Member KIF3C Regulates Microtubule Dynamics and Is Required for Axon Growth and Regeneration

Journal of Neuroscience, 2013

Axon regeneration after injury requires the extensive reconstruction, reorganization, and stabili... more Axon regeneration after injury requires the extensive reconstruction, reorganization, and stabilization of the microtubule cytoskeleton in the growth cones. Here, we identify KIF3C as a key regulator of axonal growth and regeneration by controlling microtubule dynamics and organization in the growth cone. KIF3C is developmentally regulated. Rat embryonic sensory axons and growth cones contain undetectable levels of KIF3C protein that is locally translated immediately after injury. In adult neurons, KIF3C is axonally transported from the cell body and is enriched at the growth cone where it preferentially binds to tyrosinated microtubules. Functionally, the interaction of KIF3C with EB3 is necessary for its localization at the microtubule plus-ends in the growth cone. Depletion of KIF3C in adult neurons leads to an increase in stable, overgrown and looped microtubules because of a strong decrease in the microtubule frequency of catastrophes, suggesting that KIF3C functions as a microtubule-destabilizing factor. Adult axons lacking KIF3C, by RNA interference or KIF3C gene knockout , display an impaired axonal outgrowth in vitro and a delayed regeneration after injury both in vitro and in vivo. Murine KIF3C knockout embryonic axons grow normally but do not regenerate after injury because they are unable to locally translate KIF3C. These data show that KIF3C is an injury-specific kinesin that contributes to axon growth and regeneration by regulating and organizing the microtubule cytoskeleton in the growth cone.

Research paper thumbnail of MAP1B-dependent Rac activation is required for AMPA receptor endocytosis during long-term depression

The EMBO Journal, 2013

The microtubule-associated protein 1B (MAP1B) plays critical roles in neurite growth and synapse ... more The microtubule-associated protein 1B (MAP1B) plays critical roles in neurite growth and synapse maturation during brain development. This protein is well expressed in the adult brain. However, its function in mature neurons remains unknown. We have used a genetically modified mouse model and shRNA techniques to assess the role of MAP1B at established synapses, bypassing MAP1B functions during neuronal development. Under these conditions, we found that MAP1B deficiency alters synaptic plasticity by specifically impairing long-term depression (LTD) expression. Interestingly, this is due to a failure to trigger AMPA receptor endocytosis and spine shrinkage during LTD. These defects are accompanied by an impaired targeting of the Rac1 activator Tiam1 at synaptic compartments. Accordingly, LTD and AMPA receptor endocytosis are restored in MAP1B-deficient neurons by providing additional Rac1. Therefore, these results indicate that the MAP1B-Tiam1-Rac1 relay is essential for spine structural plasticity and removal of AMPA receptors from synapses during LTD. This work highlights the importance of MAPs as signalling hubs controlling the actin cytoskeleton and receptor trafficking during plasticity in mature neurons.

Research paper thumbnail of MAP1B binds to the NMDA receptor subunit NR3A and affects NR3A protein concentrations

Neuroscience Letters, 2010

Incorporation of the N-methyl-d-aspartate receptor (NMDAR) subunit NR3A into functional NMDARs re... more Incorporation of the N-methyl-d-aspartate receptor (NMDAR) subunit NR3A into functional NMDARs results in reduced channel conductance and Ca(2+) permeability. To further investigate the function of NR3A, we have set out to characterize its intracellular binding partners. Here, we report a novel protein interaction between NR3A and microtubule associated-protein (MAP) 1B, which both are localized to dendritic shafts and filopodia. NR3A protein levels were increased in MAP1B deficient (-/-) mice, with a corresponding decrease in NR1 levels, but the fraction of filopodia immunoreactive for NR3A was equal in cells from -/- and wild type (WT) mice. NR3A has previously been shown to interact with another member of the MAP1 family, MAP1S. We showed that MAP1S binds to microtubules in a similar manner as MAP1B, and suggest that MAP1S and MAP1B both are involved in regulating trafficking of NR3A-containing NMDAR.

Research paper thumbnail of MAP1B Regulates Axonal Development by Modulating Rho-GTPase Rac1 Activity

Molecular Biology of the Cell, 2010

Cultured neurons obtained from MAP1B-deficient mice have a delay in axon outgrowth and a reduced ... more Cultured neurons obtained from MAP1B-deficient mice have a delay in axon outgrowth and a reduced rate of axonal elongation compared with neurons from wild-type mice. Here we show that MAP1B deficiency results in a significant decrease in Rac1 and cdc42 activity and a significant increase in Rho activity. We found that MAP1B interacted with Tiam1, a guanosine nucleotide exchange factor for Rac1. The decrease in Rac1/cdc42 activity was paralleled by decreases in the phosphorylation of the downstream effectors of these proteins, such as LIMK-1 and cofilin. The expression of a constitutively active form of Rac1, cdc42, or Tiam1 rescued the axon growth defect of MAP1B-deficient neurons. Taken together, these observations define a new and crucial function of MAP1B that we show to be required for efficient cross-talk between microtubules and the actin cytoskeleton during neuronal polarization.

Research paper thumbnail of Microtubule-associated Protein 1B (MAP1B) Is Required for Dendritic Spine Development and Synaptic Maturation

Journal of Biological Chemistry, 2011

Background: Microtubule-associated protein 1B (MAP1B) is a protein that is prominently expressed ... more Background: Microtubule-associated protein 1B (MAP1B) is a protein that is prominently expressed during early neuronal development but in adult brain remains in areas with high synaptic plasticity. Results: MAP1B plays an important role in dendritic spine formation and synaptic maturation. Conclusion: A novel function for MAP1B in regulating dendritic spine morphology and synaptic function is indicated. Significance: MAP1B could contribute to adult brain plasticity.

Research paper thumbnail of Microtubule-Associated Protein 1B Interaction with Tubulin Tyrosine Ligase Contributes to the Control of Microtubule Tyrosination

Developmental Neuroscience, 2007

Research paper thumbnail of The role of the VQIVYK peptide in tau protein phosphorylation

Journal of Neurochemistry, 2007

Although it remains unclear whether they are related to one another, tau aggregation and phosphor... more Although it remains unclear whether they are related to one another, tau aggregation and phosphorylation are the main pathological hallmarks of the neuronal disorders known as tauopathies. The capacity to aggregate is impaired in a variant of the tau 3R isoform that lacks residues 306-311 (nomenclature for the largest CNS tau isoform) and hence, we have taken advantage of this feature to study how phosphorylation and aggregation may be related as well as the role of this six amino acid peptide (VQIVYK). Through these analyses, we found that the phosphorylation of the tau variant was higher than that of the complete tau protein and that not only the deletion of these residues, but also the interaction of these residues, in tau 3R, with thioflavin-S augmented tau phosphorylation by glycogen synthase kinase 3. In addition, the binding of the peptide containing the residues 306-311 to the whole tau protein provoked an increase in tau phosphorylation. This observation could be physiologically relevant as may suggest that tau-tau interactions, through those residues, facilitate tau phosphorylation. In summary, our data indicate that deletion of residues VQIVYK, in tau protein produces an increase in tau phosphorylation, without tau aggregation, because the VQIVYK peptide, that favors aggregation, is missing. On the other hand, when the whole tau protein interacts with thioflavin-S or the peptide VQIVYK, an increase in both aggregation and phosphorylation occurs.

Research paper thumbnail of Role of MAP1B in hipocampal synaptic plasticity

Research paper thumbnail of Polarized trafficking: the palmitoylation cycle distributes cytoplasmic proteins to distinct neuronal compartments

Current Opinion in Cell Biology

In neurons, polarized cargo distribution occurs mainly between the soma and axonal and dendritic ... more In neurons, polarized cargo distribution occurs mainly between the soma and axonal and dendritic compartments, and requires coordinated regulation of cytoskeletal remodeling and membrane trafficking. The Golgi complex plays a critical role during neuronal polarization and secretory trafficking has been shown to differentially transport proteins to both axons and dendrites. Besides the Golgi protein sorting, recent data revealed that palmitoylation cycles are an efficient mechanism to localize cytoplasmic, non-transmembrane proteins to particular neuronal compartments, such as the newly formed axon. Palmitoylation allows substrate proteins to bind to and ride with Golgi-derived secretory vesicles to all neuronal compartments. By allowing cytoplasmic proteins to 'hitchhike' on transport carriers in a non-polarized fashion, compartmentalized depalmitoylation may act as a selective retention mechanism.

Research paper thumbnail of Feedback-Driven Mechanisms between Microtubules and the Endoplasmic Reticulum Instruct Neuronal Polarity

Neuron

Highlights d ER tubules localize to the axon, and ER cisternae are retained in the soma d Localiz... more Highlights d ER tubules localize to the axon, and ER cisternae are retained in the soma d Localization of axonal ER depends on ER-shaping proteins and the MT cytoskeleton d ER-MT crosstalk stabilizes both ER tubules and MTs in the axon d ER-MT crosstalk is critical for neuronal polarity

Research paper thumbnail of Microtubule Organization and Microtubule-Associated Proteins (MAPs)

Dendrites, 2016

Dendrites have a unique microtubule organization. In vertebrates, dendritic microtubules are orga... more Dendrites have a unique microtubule organization. In vertebrates, dendritic microtubules are organized in antiparallel bundles, oriented with their plus ends either pointing away or toward the soma. The mixed microtubule arrays control intracellular trafficking and local signaling pathways, and are essential for dendrite development and function. The organization of microtubule arrays largely depends on the combined function of different microtubule regulatory factors or generally named microtubule-associated proteins (MAPs). Classical MAPs, also called structural MAPs, were identified more than 20 years ago based on their ability to bind to and copurify with microtubules. Most classical MAPs bind along the microtubule lattice and regulate microtubule polymerization, bundling, and stabilization. Recent evidences suggest that classical MAPs also guide motor protein transport, interact with the actin cytoskeleton, and act in various neuronal signaling networks. Here, we give an overview of microtubule organization in dendrites and the role of classical MAPs in dendrite development, dendritic spine formation, and synaptic plasticity.

Research paper thumbnail of Three-Step Model for Polarized Sorting of KIF17 into Dendrites

Current Biology, 2016

Highlights d Cargo binding relieves autoinhibition of KIF17 in living cells d KIF17-bound cargo d... more Highlights d Cargo binding relieves autoinhibition of KIF17 in living cells d KIF17-bound cargo does not autonomously target dendrites d KIF17-bound cargoes enter the axon but anchor at the AIS d Dynein redirects KIF17-bound cargo into dendrites

Research paper thumbnail of Dendrites In Vitro and In Vivo Contain Microtubules of Opposite Polarity and Axon Formation Correlates with Uniform Plus-End-Out Microtubule Orientation

Journal of Neuroscience, 2016

In cultured vertebrate neurons, axons have a uniform arrangement of microtubules with plus-ends d... more In cultured vertebrate neurons, axons have a uniform arrangement of microtubules with plus-ends distal to the cell body (plus-end-out), whereas dendrites contain mixed polarity orientations with both plus-end-out and minus-end-out oriented microtubules. Rather than non-uniform microtubules, uniparallel minus-end-out microtubules are the signature of dendrites in Drosophila and Caenorhabditis elegans neurons. To determine whether mixed microtubule organization is a conserved feature of vertebrate dendrites, we used live-cell imaging to systematically analyze microtubule plus-end orientations in primary cultures of rat hippocampal and cortical neurons, dentate granule cells in mouse organotypic slices, and layer 2/3 pyramidal neurons in the somatosensory cortex of living mice. In vitro and in vivo, all microtubules had a plus-end-out orientation in axons, whereas microtubules in dendrites had mixed orientations. When dendritic microtubules were severed by laser-based microsurgery, we detected equal numbers of plus-and minus-end-out microtubule orientations throughout the dendritic processes. In dendrites, the minus-end-out microtubules were generally more stable and comparable with plus-end-out microtubules in axons. Interestingly, at early stages of neuronal development in nonpolarized cells, newly formed neurites already contained microtubules of opposite polarity, suggesting that the establishment of uniform plus-end-out microtubules occurs during axon formation. We propose a model in which the selective formation of uniform plus-end-out microtubules in the axon is a critical process underlying neuronal polarization.

Research paper thumbnail of Tau regulates the localization and function of End Binding proteins in neuronal cells

SpringerPlus, 2015

MicroRNAs (miRNAs) are short, 22-25 nucleotide long transcripts that may suppress entire signalin... more MicroRNAs (miRNAs) are short, 22-25 nucleotide long transcripts that may suppress entire signaling pathways by interacting with the 3'-untranslated region (3'-UTR) of coding mRNA targets, interrupting translation and inducing degradation of these targets. The long 3'-UTRs of brain transcripts compared to other tissues predict important roles for brain miRNAs. Supporting this notion, we found that brain miRNAs co-evolved with their target transcripts, that non-coding pseudogenes with miRNA recognition elements compete with brain coding mRNAs on their miRNA interactions, and that Single Nucleotide Polymorphisms (SNPs) on such pseudogenes are enriched in mental diseases including autism and schizophrenia, but not Alzheimer's disease (AD). Focusing on evolutionarily conserved and primate-specifi c miRNA controllers of cholinergic signaling ('CholinomiRs'), we fi nd modifi ed CholinomiR levels in the brain and/or nucleated blood cells of patients with AD and Parkinson's disease, with treatment-related diff erences in their levels and prominent impact on the cognitive and anti-infl ammatory consequences of cholinergic signals. Examples include the acetylcholinesterase (AChE)-targeted evolutionarily conserved miR-132, whose levels decline drastically in the AD brain. Furthermore, we found that interruption of AChE mRNA's interaction with the primatespecifi c CholinomiR-608 in carriers of a SNP in the AChE's miR-608 binding site induces domino-like eff ects that reduce the levels of many other miR-608 targets. Young, healthy carriers of this SNP express 40% higher brain AChE activity than others, potentially aff ecting the responsiveness to AD's anti-AChE therapeutics, and show elevated trait anxiety, infl ammation and hypertension. Non-coding regions aff ecting miRNA-target interactions in neurodegenerative brains thus merit special attention.

Research paper thumbnail of Tau regulates the localization and function of End-binding proteins 1 and 3 (EB1/3) in developing neuronal cells

Journal of neurochemistry, Jan 11, 2015

The axonal microtubule-associated protein (MAP) tau is a well-known regulator of microtubule stab... more The axonal microtubule-associated protein (MAP) tau is a well-known regulator of microtubule stability in neurons. However, the putative interplay between tau and End-binding proteins 1 and 3 (EB1/3), the core microtubule plus-end tracking proteins (+TIPs), has not been elucidated yet. Here we show that a crosstalk between tau and EB1/3 exists in developing neuronal cells. Tau and EBs partially colocalize at extending neurites of N1E-115 neuroblastoma cells and axons of primary hippocampal neurons, as shown by confocal immunofluorescence analyses. Tau downregulation leads to a reduction of EB1/3 comet length, as observed in shRNA-stably depleted neuroblastoma cells and TAU-/- neurons. EB1/3 localization depends on the expression levels and localization of tau protein. Overexpression of tau at high levels induces EBs relocalization to microtubule bundles at extending neurites of N1E-115 cells. In differentiating primary neurons, tau is required for the proper accumulation of EBs at s...

Research paper thumbnail of MAP1B regulates microtubule dynamics by sequestering EB1/3 in the cytosol of developing neuronal cells

The EMBO Journal, 2013

MAP1B, a structural microtubule (MT)-associated protein highly expressed in developing neurons, p... more MAP1B, a structural microtubule (MT)-associated protein highly expressed in developing neurons, plays a key role in neurite and axon extension. However, not all molecular mechanisms by which MAP1B controls MT dynamics during these processes have been revealed. Here, we show that MAP1B interacts directly with EB1 and EB3 (EBs), two core 'microtubule plus-end tracking proteins' (+TIPs), and sequesters them in the cytosol of developing neuronal cells. MAP1B overexpression reduces EBs binding to plus-ends, whereas MAP1B downregulation increases binding of EBs to MTs. These alterations in EBs behaviour lead to changes in MT dynamics, in particular overstabilization and looping, in growth cones of MAP1B-deficient neurons. This contributes to growth cone remodelling and a delay in axon outgrowth. Together, our findings define a new and crucial role of MAP1B as a direct regulator of EBs function and MT dynamics during neurite and axon extension. Our data provide a new layer of MT regulation: a classical MAP, which binds to the MT lattice and not to the end, controls effective concentration of core +TIPs thereby regulating MTs at their plus-ends.

Research paper thumbnail of Acetylsalicylic acid decreases tau phosphorylation at serine 422

Neuroscience Letters, 2006

Tau protein pathology in Alzheimer's disease is characterized by the hyperphosphorylation of tau ... more Tau protein pathology in Alzheimer's disease is characterized by the hyperphosphorylation of tau at some specific sites. One of these sites is serine 422 which modification has been correlated with a possible toxic effect of phosphotau in neural cells. In this work, we have found that in the presence of acetylsalicylic acid, at a concentration like that used for anti-inflammatory treatments, tau phosphorylation at serine 422 decreases.