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Autor/a:
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García-Morales, Victoria; Rodríguez-Bey, Guillermo; Gómez-Pérez, Laura; Domínguez-Vías, Germán; González-Forero, David; Portillo, Federico; Campos-Caro, Antonio; Gento-Caro, Ángela; Issaoui, Noura; Soler i Tatché, Rosa Ma.; Garcera, Ana; Moreno-López, Bernardo
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Notas:
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Disruption in membrane excitability contributes to malfunction and differential vulnerability of specific neuronal subpopulations in a number of neurological diseases. The adaptor protein p11, and background potassium channel TASK1, have overlapping distributions in the CNS. Here, we report that the transcription factor Sp1 controls p11 expression, which impacts on excitability by hampering functional expression of TASK1. In the SOD1-G93A mouse model of ALS, Sp1-p11-TASK1 dysregulation contributes to increased excitability and vulnerability of motor neurons. Interference with either Sp1 or p11 is neuroprotective, delaying neuron loss and prolonging lifespan in this model. Nitrosative stress, a potential factor in human neurodegeneration, stimulated Sp1 expression and human p11 promoter activity, at least in part, through a Sp1-binding site. Disruption of Sp1 or p11 also has neuroprotective effects in a traumatic model of motor neuron degeneration. Together our work suggests the Sp1-p11-TASK1 pathway is a potential target for treatment of degeneration of motor neurons.
Funding grants: SAF2008-01415 (MICINN/FEDER), SAF2011-23633 (MICINN), BFU2015-71422-R (MINECO/FEDER), PI14/00060 (ISCIII/FEDER) from Spain’s Government, as well as P07-CTS-02606, P09-CTS-5445, and P11-CTS-7281 (CICE/FEDER) from Junta de Andalucía, Spain. We thank Dr. Douglas A. Bayliss (University of Virginia, USA) for kindly providing the knock-out mice, Drs. Carmen Castro (University of Cadiz, Spain) and Sergey Kasparov (University of Bristol, UK) for supervision on the initial western blotting experiments and on viral constructions and production, respectively, and Ms. Lucia Molanes, Ms. Eugenia Gomez and Mr. Antonio Torres for their skillful technical assistance. We thank Elaine Lilly, Ph.D. (Writer's First Aid), for English language revision. |
