Browsing by Author "Huerta, Hernan"

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    Necroptosis inhibition counteracts neurodegeneration, memory decline, and key hallmarks of aging, promoting brain rejuvenation
    (2023) Arrazola, Macarena S.; Lira, Matias; Veliz-Valverde, Felipe; Quiroz, Gabriel; Iqbal, Somya; Eaton, Samantha L.; Lamont, Douglas J.; Huerta, Hernan; Ureta, Gonzalo; Bernales, Sebastian; Cardenas, J. Cesar; Cerpa, Waldo; Wishart, Thomas M.; Court, Felipe A.
    Age is the main risk factor for the development of neurodegenerative diseases. In the aged brain, axonal degeneration is an early pathological event, preceding neuronal dysfunction, and cognitive disabilities in humans, primates, rodents, and invertebrates. Necroptosis mediates degeneration of injured axons, but whether necroptosis triggers neurodegeneration and cognitive impairment along aging is unknown. Here, we show that the loss of the necroptotic effector Mlkl was sufficient to delay age-associated axonal degeneration and neuroinflammation, protecting against decreased synaptic transmission and memory decline in aged mice. Moreover, short-term pharmacologic inhibition of necroptosis targeting RIPK3 in aged mice, reverted structural and functional hippocampal impairment, both at the electrophysiological and behavioral level. Finally, a quantitative proteomic analysis revealed that necroptosis inhibition leads to an overall improvement of the aged hippocampal proteome, including a subclass of molecular biofunctions associated with brain rejuvenation, such as long-term potentiation and synaptic plasticity. Our results demonstrate that necroptosis contributes to age-dependent brain degeneration, disturbing hippocampal neuronal connectivity, and cognitive function. Therefore, necroptosis inhibition constitutes a potential geroprotective strategy to treat age-related disabilities associated with memory impairment and cognitive decline.
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    The Ski Protein is Involved in the Transformation Pathway of Aurora Kinase A
    (WILEY, 2016) Rivas, Solange; Armisen, Ricardo; Rojas, Diego A.; Maldonado, Edio; Huerta, Hernan; Tapia, Julio C.; Espinoza, Jaime; Colombo, Alicia; Michea, Luis; Hayman, Michael J.; Marcelain, Katherine
    Oncogenic kinase Aurora A (AURKA) has been found to be overexpresed in several tumors including colorectal, breast, and hematological cancers. Overexpression of AURKA induces centrosome amplification and aneuploidy and it is related with cancer progression and poor prognosis. Here we show that AURKA phosphorylates in vitro the transcripcional co-repressor Ski on aminoacids Ser326 and Ser383. Phosphorylations on these aminoacids decreased Ski protein half-life. Reduced levels of Ski resulted in centrosomes amplification and multipolar spindles formation, same as AURKA overexpressing cells. Importantly, overexpression of Ski wild type, but not S326D and S383D mutants inhibited centrosome amplification and cellular transformation induced by AURKA. Altogether, these results suggest that the Ski protein is a target in the transformation pathway mediated by the AURKA oncogene. (C) 2015 Wiley Periodicals, Inc.