Sp1-regulated expression of p11 contributes to motor neuron degeneration by membrane insertion of TASK1

Victoria García-Morales, Guillermo Rodríguez-Bey, Laura Gómez-Pérez, Germán Domínguez-Vías, David González-Forero, Federico Portillo, Antonio Campos-Caro, Ángela Gento-Caro, Noura Issaoui, Rosa M. Soler, Ana Garcera and Bernardo Moreno-López ()
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Victoria García-Morales: Universidad de Cádiz
Guillermo Rodríguez-Bey: Universidad de Cádiz
Laura Gómez-Pérez: Universidad de Cádiz
Germán Domínguez-Vías: Universidad de Cádiz
David González-Forero: Universidad de Cádiz
Federico Portillo: Universidad de Cádiz
Antonio Campos-Caro: Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA)
Ángela Gento-Caro: Universidad de Cádiz
Noura Issaoui: Universidad de Cádiz
Rosa M. Soler: Universitat de Lleida-IRBLLEIDA
Ana Garcera: Universitat de Lleida-IRBLLEIDA
Bernardo Moreno-López: Universidad de Cádiz

Nature Communications, 2019, vol. 10, issue 1, 1-23

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11637-4

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