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

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.

MiR-128-3p Alleviates Spinal Cord Ischemia/Reperfusion Injury Associated Neuroinflammation and Cellular Apoptosis via SP1 Suppression in Rat

“…A previous study also noted increased SP1 expression in the cortex after brain I/R damage and in primary neurons post-OGD/R ( Sun et al, 2015 ), providing novel insights into the endogenous pathways that prevent ischemia-associated neuronal injury. Moreover, SP1 suppression delays neuronal loss and prolongs survival ( Garcia-Morales et al, 2019 ). Additionally, in the current study, intrathecal injection of AV-sh-SP1 not only induced comparably lower levels of SP1 and resulted in poor production of IL-6, IL-1β, TNF-α, and Bax, but also upregulated Bcl-2, improved neurological function and histological findings, dwindled TUNEL-positive cells in anterior horn, and attenuated EB leakage, in comparison with the I/R group.…”

Up-regulation of microRNA-375 ameliorates the damage of dopaminergic neurons, reduces oxidative stress and inflammation in Parkinson’s disease by inhibiting SP1

“…Except that, SP1 is dramatically up-regulated in embryonic cortical neurons in response to oxidative stress [33], and it up-regulates the expression of manganese superoxide dismutase, which protects the mitochondrion from reactive oxygen species-induced damage [34], suggesting SP1 might be a oxidative stress-induced transcription factor that represses neuronal survival in cortical neurons. Furthermore, inhibition of SP1 has been proved to delay neuron loss and prolong lifespan [35].…”

Nitric oxide controls excitatory/inhibitory balance in the hypoglossal nucleus during early postnatal development

“…In addition, inward rectification current ( I h ) up-regulates during postnatal development. Interestingly, NO increases HMNs excitability by facilitating I h current, and enhances input resistance and reduces rheobase (González-Forero et al 2007 ; Montero et al 2008 ) by at least inhibiting and/or impairing plasma membrane insertion of TASK1 channels (González-Forero et al 2007 ; García-Morales et al 2019 ). Therefore, dysregulation of NOS expression during this key period could lie behind HMN malfunctioning contributing to sudden infant death.…”

“…1 ). The infusion system was finally attached to the skull by means of an instant adhesive gel (Loctite 454, Alzet) once the end of infusion cannula was positioned near to the fourth ventricle as previously performed (García-Morales et al 2015 , 2019 ). Finally, a small incision was made at the base of the neck and stretched with a hemostat to facilitate implantation.…”

“…Obtaining samples and immunohistochemistry processing have been performed as previously described with minimal differences (García-Morales et al 2015 , 2019 ). Juvenile (P21) rats were anesthetized with chloral hydrate (0.5 g/kg; i.p.…”