Browsing by Author "Gonzalez-Billault, Christian"

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    Cholinergic abnormalities, endosomal alterations and up-regulation of nerve growth factor signaling in Niemann-Pick Type C disease
    (2012) Cabeza Huerta, Carolina Andrea; Figueroa, Alicia; Lazo Jerez, Oscar Marcelo; Galleguillos, Carolina; Pissani Alvear, Claudia; Klein, Andrés; Inestrosa Cantín, Nibaldo; Álvarez Rojas, Alejandra; Zanlungo Matsuhiro, Silvana; Bronfman C., Francisca; Gonzalez-Billault, Christian
    Abstract Background Neurotrophins and their receptors regulate several aspects of the developing and mature nervous system, including neuronal morphology and survival. Neurotrophin receptors are active in signaling endosomes, which are organelles that propagate neurotrophin signaling along neuronal processes. Defects in the Npc1 gene are associated with the accumulation of cholesterol and lipids in late endosomes and lysosomes, leading to neurodegeneration and Niemann-Pick type C (NPC) disease. The aim of this work was to assess whether the endosomal and lysosomal alterations observed in NPC disease disrupt neurotrophin signaling. As models, we used i) NPC1-deficient mice to evaluate the central cholinergic septo-hippocampal pathway and its response to nerve growth factor (NGF) after axotomy and ii) PC12 cells treated with U18666A, a pharmacological cellular model of NPC, stimulated with NGF. Results NPC1-deficient cholinergic cells respond to NGF after axotomy and exhibit increased levels of choline acetyl transferase (ChAT), whose gene is under the control of NGF signaling, compared to wild type cholinergic neurons. This finding was correlated with increased ChAT and phosphorylated Akt in basal forebrain homogenates. In addition, we found that cholinergic neurons from NPC1-deficient mice had disrupted neuronal morphology, suggesting early signs of neurodegeneration. Consistently, PC12 cells treated with U18666A presented a clear NPC cellular phenotype with a prominent endocytic dysfunction that includes an increased size of TrkA-containing endosomes and reduced recycling of the receptor. This result correlates with increased sensitivity to NGF, and, in particular, with up-regulation of the Akt and PLC-γ signaling pathways, increased neurite extension, increased phosphorylation of tau protein and cell death when PC12 cells are differentiated and treated with U18666A. Conclusions Our results suggest that the NPC cellular phenotype causes neuronal dysfunction through the abnormal up-regulation of survival pathways, which causes the perturbation of signaling cascades and anomalous phosphorylation of the cytoskeleton.
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    The impact of SARS-CoV-2 in dementia across Latin America: A call for an urgent regional plan and coordinated response
    (2020) Ibanez, Agustin; Santamaria-Garcia, Hernando; Guerrero Barragan, Alejandra; Kornhuber, Alexander; Marques Ton, Alyne Mendonca; Slachevsky, Andrea; Lucio Teixeira, Antonio; Mar Meza, Beatriz Marcela; Serrano, Cecilia M.; Cano, Carlos; Arias Gonzalez, Carolina; Gonzalez-Billault, Christian; Butler, Christopher; Bustin, Julian; Duran-Aniotz, Claudia; Acosta, Daisy; Matallana, Diana L.; Acosta-Alvear, Diego; Trepel, Dominic; Franca Resende, Elisa De Paula; Ferreira Oliveira, Fabricio; Ibanez, Francisco; De Felice, Fernanda G.; Navarrete, Gorka; Tarnanas, Ioannis; Meier, Irene B.; Smid, Jerusa; Llibre-Guerra, Jorge; Llibre-Rodriguez, Juan J.; Fajersztajn, Lais; Takada, Leonel Tadao; Duque, Lissette; de Oliveira, Maira Okada; Camargos Bicalho, Maria Aparecida; Isabel Behrens, Maria; Pintado-Caipa, Maritza; Parra, Mario; Wilson, Maxwell Z.; De la Cruz Puebla, Myriam; Custodio, Nilton; Santibanez, Rodrigo; Serafim, Rodrigo Bernardo; Tavares, Ronnielly Melo; Pina Escudero, Stefanie Danielle; Leon Rodriguez, Tomas; Dawson, Walter; Miller, Bruce L.; Kosik, Kenneth S.
    The SARS-CoV-2 global pandemic will disproportionately impact countries with weak economies and vulnerable populations including people with dementia. Latin American and Caribbean countries (LACs) are burdened with unstable economic development, fragile health systems, massive economic disparities, and a high prevalence of dementia. Here, we underscore the selective impact of SARS-CoV-2 on dementia among LACs, the specific strain on health systems devoted to dementia, and the subsequent effect of increasing inequalities among those with dementia in the region. Implementation of best practices for mitigation and containment faces particularly steep challenges in LACs. Based upon our consideration of these issues, we urgently call for a coordinated action plan, including the development of inexpensive mass testing and multilevel regional coordination for dementia care and related actions. Brain health diplomacy should lead to a shared and escalated response across the region, coordinating leadership, and triangulation between governments and international multilateral networks.
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    Wnt5a modulates dendritic spine dynamics through the regulation of Cofilin via small Rho GTPase activity in hippocampal neurons
    (2021) Vallejo, Daniela; Lindsay, Carolina B.; Gonzalez-Billault, Christian; Inestrosa, Nibaldo C.
    Dendritic spines are small, actin-rich protrusions that act as the receiving sites of most excitatory inputs in the central nervous system. The remodeling of the synapse architecture is mediated by actin cytoskeleton dynamics, a process precisely regulated by the small Rho GTPase family. Wnt ligands exert their presynaptic and postsynaptic effects during formation and consolidation of the synaptic structure. Specifically, Wnt5a has been identified as an indispensable synaptogenic factor for the regulation and organization of the postsynaptic side; however, the molecular mechanisms through which Wnt5a induces morphological changes resulting from actin cytoskeleton dynamics within dendritic spines remain unclear. In this work, we employ primary rat hippocampal cultures and HT22 murine hippocampal neuronal cell models, molecular and pharmacological tools, and fluorescence microscopy (laser confocal and epifluorescence) to define the Wnt5a-induced molecular signaling involved in postsynaptic remodeling mediated via the regulation of the small Rho GTPase family. We report that Wnt5a differentially regulates the phosphorylation of Cofilin in neurons through both Ras-related C3 botulinum toxin substrate 1 and cell division cycle 42 depending on the subcellular compartment and the extracellular calcium levels. Additionally, we demonstrate that Wnt5a increases the density of dendritic spines and promotes their maturation via Ras-related C3 botulinum toxin substrate 1. Accordingly, we find that Wnt5a requires the combined activation of small Rho GTPases to increase the levels of filamentous actin, thus promoting the stability of actin filaments. Altogether, these results provide evidence for a new mechanism by which Wnt5a may target actin dynamics, thereby regulating the subsequent morphological changes in dendritic spine architecture.