Browsing by Author "Sierralta, Jimena"

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    BAX inhibitor-1 regulates autophagy by controlling the IRE1α branch of the unfolded protein response
    (2011) Castillo, Karen; Rojas-Rivera, Diego; Lisbona, Fernanda; Caballero, Benjamin; Nassif, Melissa; Court, Felipe A.; Schuck, Sebastian; Ibar, Consuelo; Walter, Peter; Sierralta, Jimena; Glavic, Alvaro; Hetz, Claudio
    Both autophagy and apoptosis are tightly regulated processes playing a central role in tissue homeostasis. Bax inhibitor 1 (BI-1) is a highly conserved protein with a dual role in apoptosis and endoplasmic reticulum (ER) stress signalling through the regulation of the ER stress sensor inositol requiring kinase 1 alpha (IRE1 alpha). Here, we describe a novel function of BI-1 in the modulation of autophagy. BI-1-deficient cells presented a faster and stronger induction of autophagy, increasing LC3 flux and autophagosome formation. These effects were associated with enhanced cell survival under nutrient deprivation. Repression of autophagy by BI-1 was dependent on cJun-N terminal kinase (JNK) and IRE1 alpha expression, possibly due to a displacement of TNF-receptor associated factor-2 (TRAF2) from IRE1 alpha. Targeting BI-1 expression in flies altered autophagy fluxes and salivary gland degradation. BI-1 deficiency increased flies survival under fasting conditions. Increased expression of autophagy indicators was observed in the liver and kidney of bi-1-deficient mice. In summary, we identify a novel function of BI-1 in multicellular organisms, and suggest a critical role of BI-1 as a stress integrator that modulates autophagy levels and other interconnected homeostatic processes. The EMBO Journal (2011) 30, 4465-4478. doi:10.1038/emboj.2011.318; Published online 16 September 2011
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    Dlg Is Required for Short-Term Memory and Interacts with NMDAR in the Drosophila Brain
    (2022) Bertin, Francisca; Moya-Alvarado, Guillermo; Quiroz-Manriquez, Eduardo; Ibacache, Andres; Kohler-Solis, Andres; Oliva, Carlos; Sierralta, Jimena
    The vertebrates' scaffold proteins of the Dlg-MAGUK family are involved in the recruitment, clustering, and anchoring of glutamate receptors to the postsynaptic density, particularly the NMDA subtype glutamate-receptors (NRs), necessary for long-term memory and LTP. In Drosophila, the only gene of the subfamily generates two main products, dlgA, broadly expressed, and dlgS97, restricted to the nervous system. In the Drosophila brain, NRs are expressed in the adult brain and are involved in memory, however, the role of Dlg in these processes and its relationship with NRs has been scarcely explored. Here, we show that the dlg mutants display defects in short-term memory in the olfactory associative-learning paradigm. These defects are dependent on the presence of DlgS97 in the Mushroom Body (MB) synapses. Moreover, Dlg is immunoprecipitated with NRs in the adult brain. Dlg is also expressed in the larval neuromuscular junction (NMJ) pre and post-synaptically and is important for development and synaptic function, however, NR is absent in this synapse. Despite that, we found changes in the short-term plasticity paradigms in dlg mutant larval NMJ. Together our results show that larval NMJ and the adult brain relies on Dlg for short-term memory/plasticity, but the mechanisms differ in the two types of synapses.
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    The transcription factor SoxD controls neuronal guidance in the Drosophila visual system
    (2018) Contreras, Esteban G. ; Palominos, Tomás ; Glavic, Álvaro ; Brand, Andrea H. ; Sierralta, Jimena ; Oliva, Carlos
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    Whole-brain neuronal MCT2 lactate transporter expression links metabolism to human brain structure and function
    (National Academy of Sciences, 2022) Medel Sierralta, Vicente Nicolas; Crossley Karmelic, Nicolas Andrés; Gajardo, Ivana; Muller, Eli; Barros L., Felipe; Shine, James N.; Sierralta, Jimena
    Brain activity is constrained by local availability of chemical energy, which is generatedthrough compartmentalized metabolic processes. By analyzing data of whole humanbrain gene expression, we characterize the spatial distribution of seven glucose andmonocarboxylate membrane transporters that mediate astrocyte–neuron lactate shuttletransfer of energy. We found that the gene coding for neuronal MCT2 is the onlygene enriched in cerebral cortex where its abundance is inversely correlated withcortical thickness. Coexpression network analysis revealed that MCT2 was the onlygene participating in an organized gene cluster enriched in K+dynamics. Indeed, theexpression of KATPsubunits, which mediate lactate increases with spiking activity, isspatially coupled to MCT2 distribution. Notably, MCT2 expression correlated withfluorodeoxyglucose positron emission tomography task-dependent glucose utilization.Finally, the MCT2 messenger RNA gradient closely overlaps with functional MRI brainregions associated with attention, arousal, and stress. Our results highlight neuronalMCT2 lactate transporter as a key component of the cross-talk between astrocytes andneurons and a link between metabolism, cortical structure, and state-dependent brain function.