Browsing by Author "Hernandez, Diego E."

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    Axonal Degeneration Is Mediated by Necroptosis Activation
    (2019) Arrazola, Macarena S.; Saquel, Cristian; Catalan, Romina J.; Barrientos, Sebastian A.; Hernandez, Diego E.; Martinez, Nicolas W.; Catenaccio, Alejandra; Court, Felipe A.
    Axonal degeneration, which contributes to functional impairment in several disorders of the nervous system, is an important target for neuroprotection. Several individual factors and subcellular events have been implicated in axonal degeneration, but researchers have so far been unable to identify an integrative signaling pathway activating this self-destructive process. Through pharmacological and genetic approaches, we tested whether necroptosis, a regulated cell-death mechanism implicated in the pathogenesis of several neurodegenerative diseases, is involved in axonal degeneration. Pharmacological inhibition of the necroptotic kinase RIPK1 using necrostatin-1 strongly delayed axonal degeneration in the peripheral nervous system and CNS of wild-type mice of either sex and protected in vitro sensory axons from degeneration after mechanical and toxic insults. These effects were also observed after genetic knock-down of RIPK3, a second key regulator of necroptosis, and the downstream effector MLKL (Mixed Lineage Kinase Domain-Like). RIPK1 inhibition prevented mitochondrial fragmentation in vitro and in vivo, a typical feature of necrotic death, and inhibition of mitochondrial fission by Mdivi also resulted in reduced axonal loss in damaged nerves. Furthermore, electrophysiological analysis demonstrated that inhibition of necroptosis delays not only the morphological degeneration of axons, but also the loss of their electrophysiological function after nerve injury. Activation of the necroptotic pathway early during injury-induced axonal degeneration was made evident by increased phosphorylation of the downstream effector MLKL. Our results demonstrate that axonal degeneration proceeds by necroptosis, thus defining a novel mechanistic framework in the axonal degenerative cascade for therapeutic interventions in a wide variety of conditions that lead to neuronal loss and functional impairment.
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    STI571 prevents apoptosis, tau phosphorylation and behavioural impairments induced by Alzheimer's beta-amyloid deposits
    (OXFORD UNIV PRESS, 2008) Cancino, Gonzalo I.; Toledo, Enrique M.; Leal, Nancy R.; Hernandez, Diego E.; Yevenes, L. Fernanda; Inestrosa, Nibaldo C.; Alvarez, Alejandra R.
    There is evidence that amyloid beta-protein (A beta) deposits or A intermediates trigger pathogenic factors in Alzheimers disease patients. We have previously reported that c-Abl kinase activation involved in cell signalling regulates the neuronal death response to A fibrils (A beta(f)). In the present study we investigated the therapeutic potential of the selective c-Abl inhibitor STI57I on both the intrahippocampal injection of Af and APPsw/PSENI Delta E9 transgenic mice Alzheimers disease models. Injection of A beta(f) induced an increase in the numbers of p73 and c-Abl immunoreactive cells in the hippocampal area near to the lesion. Chronic intraperitoneal administration of STI571 reduced the rat behavioural deficit induced by A beta(f), as well as apoptosis and tau phosphorylation. Our in vitro studies suggest that inhibition of the c-Abl/p73 signalling pathway is the mechanism underlying of the effects of STI571 on A beta-induced apoptosis for the following reasons: (i) A beta(f) induces p73 phosphorylation, the TAp73 isoform levels increase so as to enhance its proapoptotic function, and all these effects where reduced by STI571; (ii) c-Abl kinase activity is required for neuronal apoptosis and (iii) STI571 prevents the A beta-induced increase in the expression of apoptotic genes. Furthermore, in the A-injected area there was a huge increase in phosphorylated p73 and a larger number of TAp73-positive cells, with these changes being prevented by STI571 coinjection. Moreover, the intraperitoneal administration of STI571 rescued the cognitive decline in APPsw/PSENI Delta E9 mice, p73 phosphorylation, tau phosphorylation and caspase-3 activation in neurons around A beta deposits. Besides, we observed a decrease in the number and size of A beta deposits in the APPsw/PSENI Delta E9-STI571-treated mice. These results are consistent with the role of the c-Abl/p73 signalling pathway in A beta neurodegeneration, and suggest that STI571-like compounds would be effective in therapeutic treatments of Alzheimer disease.