Browsing by Author "Vargas, Lina M."

Now showing 1 - 3 of 3
  • No Thumbnail Available
    Item
    c-Abl Deficiency Provides Synaptic Resiliency Against Aβ-Oligomers
    (2019) Gutierrez, Daniela A.; Vargas, Lina M.; Chandia-Cristi, America; de la Fuente, Catalina; Leal, Nancy; Alvarez, Alejandra R.
    Spine pathology has been implicated in the early onset of Alzheimer & x2019;s disease (AD), where A & x3b2;-Oligomers (A & x3b2;Os) cause synaptic dysfunction and loss. Previously, we described that pharmacological inhibition of c-Abl prevents A & x3b2;Os-induced synaptic alterations. Hence, this kinase seems to be a key element in AD progression. Here, we studied the role of c-Abl on dendritic spine morphological changes induced by A & x3b2;Os using c-Abl null neurons (c-Abl-KO). First, we characterized the effect of c-Abl deficiency on dendritic spine density and found that its absence increases dendritic spine density. While A & x3b2;Os-treatment reduces the spine number in both wild-type (WT) and c-Abl-KO neurons, A & x3b2;Os-driven spine density loss was not affected by c-Abl. We then characterized A & x3b2;Os-induced morphological changes in dendritic spines of c-Abl-KO neurons. A & x3b2;Os induced a decrease in the number of mushroom spines in c-Abl-KO neurons while preserving the populations of immature stubby, thin, and filopodia spines. Furthermore, synaptic contacts evaluated by PSD95/Piccolo clustering and cell viability were preserved in A & x3b2;Os-exposed c-Abl-KO neurons. In conclusion, our results indicate that in the presence of A & x3b2;Os c-Abl participates in synaptic contact removal, increasing susceptibility to A & x3b2;Os damage. Its deficiency increases the immature spine population reducing A & x3b2;Os-induced synapse elimination. Therefore, c-Abl signaling could be a relevant actor in the early stages of AD.
  • Thumbnail Image
    Item
    Imatinib therapy blocks cerebellar apoptosis and improves neurological symptoms in a mouse model of Niemann-Pick type C disease
    (WILEY, 2008) Alvarez, Alejandra R.; Klein, Andres; Castro, Juan; Cancino, Gonzalo I.; Amigo, Julio; Mosqueira, Matias; Vargas, Lina M.; Yevenes, L. Fernanda; Bronfman, Francisca C.; Zanlungo, Silvana
    Niemann-Pick type C (NPC) disease is a fatal autosomal recessive disorder characterized by the accumulation of free cholesterol and glycosphingo-lipids in the endosomal-lysosomal system. Patients with NPC disease have markedly progressive neuronal loss, mainly of cerebellar Purkinje neurons. There is strong evidence indicating that cholesterol accumulation and trafficking defects activate apoptosis in NPC brains. The purpose of this study was to analyze the relevance of apoptosis and particularly the proapoptotic c-Abl/p73 system in cerebellar neuron degeneration in NPC disease. We used the NPC1 mouse model to evaluate c-Abl/p73 expression and activation in the cerebellum and the effect of therapy with the c-Abl-specific inhibitor imatinib. The proapoptotic c-Abl/p73 system and the p73 target genes are expressed in the cerebellums of NPC mice. Furthermore, inhibition of c-Abl with imatinib preserved Purkinje neurons and reduced general cell apoptosis in the cerebellum, improved neurological symptoms, and increased the survival of NPC mice. Moreover, this prosurvival effect correlated with reduced mRNA levels of p73 proapoptotic target genes. Our results suggest that the c-Abl/p73 pathway is involved in NPC neurodegeneration and show that treatment with c-Abl inhibitors is useful in delaying progressive neurodegeneration, supporting the use of imatinib for clinical treatment of patients with NPC disease.
  • No Thumbnail Available
    Item
    Physiological Control of Nitric Oxide in Neuronal BACE1 Translation by Heme-Regulated eIF2α Kinase HRI Induces Synaptogenesis
    (2015) ILL-Raga, Gerard; Tajes, Marta; Busquets-Garcia, Arnau; Ramos-Fernandez, Eva; Vargas, Lina M.; Bosch-Morato, Monica; Guivernau, Biuse; Valls-Comamala, Victoria; Eraso-Pichot, Abel; Guix, Francesc X.; Fandos, Cesar; Rosen, Mark D.; Rabinowitz, Michael H.; Maldonado, Rafael; Alvarez, Alejandra R.; Ozaita, Andres; Munoz, Francisco J.
    Aims: Hippocampus is the brain center for memory formation, a process that requires synaptogenesis. However, hippocampus is dramatically compromised in Alzheimer's disease due to the accumulation of amyloid beta-peptide, whose production is initiated by beta-site APP Cleaving Enzyme 1 (BACE1). It is known that pathological stressors activate BACE1 translation through the phosphorylation of the eukaryotic initiation factor-2 alpha (eIF2 alpha) by GCN2, PERK, or PKR kinases, leading to amyloidogenesis. However, BACE1 physiological regulation is still unclear. Since nitric oxide (NO) participates directly in hippocampal glutamatergic signaling, we investigated the neuronal role of the heme-regulated eukaryotic initiation factor eIF2 alpha kinase (HRI), which can bind NO by a heme group, in BACE1 translation and its physiological consequences. Results: We found that BACE1 is expressed on glutamate activation with NO being the downstream effector by triggering eIF2 alpha phosphorylation, as it was obtained by Western blot and luciferase assay. It is due to the activation of HRI by NO as assayed by Western blot and immunofluorescence with an HRI inhibitor and HRI siRNA. BACE1 expression was early detected at synaptic spines, contributing to spine growth and consolidating the hippocampal memory as assayed with mice treated with HRI or neuronal NO synthase inhibitors. Innovation: We provide the first description that HRI and eIF2 alpha are working in physiological conditions in the brain under the control of nitric oxide and glutamate signaling, and also that BACE1 has a physiological role in hippocampal function. Conclusion: We conclude that BACE1 translation is controlled by NO through HRI in glutamatergic hippocampal synapses, where it plays physiological functions, allowing the spine growth and memory consolidation. Antioxid. Redox Signal. 22, 1295-1307.