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.
Highlights
Disruption in membrane excitability contributes to malfunction and differential vulnerability of specific neuronal subpopulations in a number of neurological diseases
The ubiquitous transcription factor Sp1 controls the expression of p11, a retention factor at the endoplasmic reticulum for TASK114, which regulates channel expression at the cell surface, fine-tuning neuronal intrinsic membrane excitability (IME) and Ca2+ influx via glutamate receptors (GluRs) and voltage-sensitive Ca2+ channels (VSCCs) (Fig. 10a)
We conclude that modulation of the Sp1–p11–TASK1 triad offers a promising strategy to minimize excitotoxic damage occurring in a multitude of neuropathologies associated with dysregulated membrane excitability and/or excitotoxic degeneration, including both acute and chronic neurodegenerative diseases7,8
Summary
Disruption in membrane excitability contributes to malfunction and differential vulnerability of specific neuronal subpopulations in a number of neurological diseases. Together our work suggests the Sp1-p11TASK1 pathway is a potential target for treatment of degeneration of motor neurons Despite their different clinical manifestations, neurodegenerative diseases share a multitude of common underlying mechanisms. The adaptor protein p11 (S100A10) could be a firm candidate to fine-tune neuronal IME by regulating plasma membrane insertion of TASK1 (TWIK-related acid-sensitive K+ subunit 1), a member of the KCNK family of two-pore-domain K+ channels. This family primarily determines passive membrane properties in mammalian cells, which confers it potential therapeutic impact. Our findings support that dysregulation of the ubiquitous transcription factor Sp1, p11, and TASK1 contributes to MN degeneration by impacting on MN IME and vulnerability
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