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Lopez-menendez C.,Institute Investigaciones Biomedicas Alberto Sols CSIC UAM | Lopez-menendez C.,CIBER ISCIII | Gamir-morralla A.,Institute Investigaciones Biomedicas Alberto Sols CSIC UAM | Gamir-morralla A.,CIBER ISCIII | And 12 more authors.
Human Molecular Genetics

Failures in neurotrophic support and signalling play key roles in Alzheimer's disease (AD) pathogenesis. We previously demonstrated that downregulation of the neurotrophin effector Kinase D interacting substrate (Kidins220) by excitotoxicity and cerebral ischaemia contributed to neuronal death. This downregulation, triggered through overactivation of N-methyl-d-aspartate receptors (NMDARs), involved proteolysis of Kidins220 by calpain and transcriptional inhibition. As excitotoxicity is at the basis of AD aetiology, we hypothesized that Kidins220 might also be downregulated in this disease. Unexpectedly, Kidins220 is augmented in necropsies from AD patients where it accumulates with hyperphosphorylated tau. This increase correlates with enhanced Kidins220 resistance to calpain processing but no higher gene transcription. Using AD brain necropsies, glycogen synthase kinase 3-β (GSK3β)-transgenic mice and cell models of AD-related neurodegeneration, we show that GSK3β phosphorylation decreases Kidins220 susceptibility to calpain proteolysis, while protein phosphatase 1 (PP1) action has the opposite effect. As altered activities of GSK3β and phosphatases are involved in tau aggregation and constitute hallmarks in AD, a GSK3β/PP1 imbalance may also contribute to Kidins220 decreased clearance, accumulation and hampered neurotrophin signalling from early stages of the disease pathogenesis. These results encourage searches for mutations in Kidins220 gene and their possible associations to dementias. Finally, our data support a model where the effects of excitotoxicity drastically differ when occurring in cerebral ischaemia versus progressively sustained toxicity along AD progression. The striking differences in Kidins220 stability resulting from chronic versus acute brain damage may also have important implications for the therapeutic intervention of neurodegenerative disorders. © The Author 2012. Published by Oxford University Press. All rights reserved. Source

Velasco S.,Membrane Biology and Axonal Repair Laboratory | Diez-Revuelta N.,Membrane Biology and Axonal Repair Laboratory | Hernandez-Iglesias T.,Research Center del Cancer CSIC | Kaltner H.,Ludwig Maximilians University of Munich | And 3 more authors.
Journal of Neurochemistry

Axon membrane glycoproteins are essential for neuronal differentiation, although the mechanisms underlying their polarized sorting and organization are poorly understood. We describe here that galectin-4 (Gal-4), a lectin highly expressed in gastrointestinal tissues and involved in epithelial glycoprotein transport, is expressed by hippocampal and cortical neurons where it is sorted to discrete segments of the axonal membrane in a microtubule- and sulfatide-dependent manner. Gal-4 knockdown retards axon growth, an effect that can be rescued by recombinant Gal-4 addition. This Gal-4 reduction, as inhibition of sulfatide synthesis does, lowers the presence and clustered organization of axon growth-promoting molecule NCAM L1 at the axon membrane. Furthermore, we find that Gal-4 interacts with L1 by specifically binding to LacNAc branch ends of L1 N-glycans. Impairing the maturation of these N-glycans precludes Gal-4/L1 association resulting in a failure of L1 membrane cluster organization. In all, Gal-4 sorts to axon plasma membrane segments by binding to sulfatide-containing microtubule-associated carriers and being bivalent, it organizes the transport of L1, and likely other axonal glycoproteins, by attaching them to the carriers through their LacNAc termini. This mechanism would underlie L1 functional organization on the plasma membrane, required for proper axon growth. Galectin-4 sorts to axon plasma membrane segments by binding to sulfatide-containing axonal carriers and, being bivalent, it organizes the transport of L1, and likely other glycoproteins, by attaching them to the same carriers specifically through their LacNAc termini. We propose that this mechanism would underlie L1 functional clustered organization on the axon membrane, required for proper axon growth. © 2013 International Society for Neurochemistry. Source

Oliviero A.,FENNSI Group | Carrasco-Lopez M.C.,FENNSI Group | Campolo M.,FENNSI Group | Perez-Borrego Y.A.,FENNSI Group | And 7 more authors.
Brain Stimulation

Background: Transcranial static magnetic field stimulation (tSMS) in humans reduces cortical excitability. Objective: The objective of this study was to determine if prolonged tSMS (2 h) could be delivered safely in humans. Safety limits for this technique have not been described. Methods: tSMS was applied for 2 h with a cylindric magnet on the occiput of 17 healthy subjects. We assessed tSMS-related safety aspects at tissue level by measuring levels of neuron-specific enolase (NSE, a marker of neuronal damage) and S100 (a marker of glial reactivity and damage). We also included an evaluation of cognitive side effects by using a battery of visuomotor and cognitive tests. Results: tSMS did not induce any significant increase in NSE or S100. No cognitive alteration was detected. Conclusions: Our data indicate that the application of tSMS is safe in healthy human subjects, at least within these parameters. © 2015 The Authors. Published by Elsevier Inc. Source

Abad-Rodriguez J.,Membrane Biology and Axonal Repair Laboratory | Diez-Revuelta N.,Membrane Biology and Axonal Repair Laboratory
Trends in Biochemical Sciences

Nervous system function relies on the capacity of neurons to organize specialized domains for impulse reception or transmission. Such a polarized architecture relies on highly discriminatory and efficient mechanisms for the transport and targeting of required molecules to their functional positions. Glycans play a central role in polarized traffic based on their extraordinary capacity to encrypt bio-information. Glycan-based interactions exquisitely regulate cargo selection, trafficking, and targeting to the axon membrane. This generates segregated functional domains, where basal nerve processes such as axon growth, synaptic activity, or myelination take place. Deciphering the details of the glycan structures and carbohydrate-binding molecules that underlie these mechanisms improves our knowledge of nerve physiology and defines novel specific approaches for neurological treatments. © 2015 Elsevier Ltd. Source

Diez-Revuelta N.,Membrane Biology and Axonal Repair Laboratory | Velasco S.,Membrane Biology and Axonal Repair Laboratory | Andre S.,Ludwig Maximilians University of Munich | Kaltner H.,Ludwig Maximilians University of Munich | And 3 more authors.
Journal of Cell Science

Serine phosphorylation of the β-galactoside-binding protein galectin-3 (Gal-3) impacts nuclear localization but has unknown consequences for extracellular activities. Herein, we reveal that the phosphorylated form of galectin-3 (pGal-3), adsorbed to substratum surfaces or to heparan sulphate proteoglycans, is instrumental in promoting axon branching in cultured hippocampal neurons by local actin destabilization. pGal-3 interacts with neural cell adhesion molecule L1, and enhances L1 association with Thy-1-rich membrane microdomains. Concomitantly, membrane-actin linker proteins ezrin-radixin-moesin (ERM) are recruited to the same membrane site via interaction with the intracellular domain of L1. We propose that the local regulation of the L1-ERM-actin pathway, at the level of the plasma membrane, underlies pGal-3-induced axon branching, and that galectin phosphorylation in situ could act as a molecular switch for the axon response to Gal-3. Source

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