Suchergebnisse

A preclinical strategy to broaden the search of potentially effective treatments in amyotrophic lateral sclerosis (ALS) relies on identifying factors controlling motor neuron (MN) excitability. These partners might be part of still unknown pathogenic pathways and/or useful for the design of new interventions to affect disease progression. In this framework, the bioactive membrane-derived phospholipid lysophosphatidic acid (LPA) affects MN excitability through LPA receptor 1 (LPA(1)). Furthermore, LPA(1) knockdown is neuroprotective in transgenic ALS SOD1-G93A mice. On this basis, we raised the hypothesis that the major LPA-synthesizing ectoenzyme, autotaxin (ATX), regulates MN excitability and is a potential target to modulate disease development in ALS mice. We show here that PF-8380, a specific ATX inhibitor, reduced intrinsic membrane excitability (IME) of hypoglossal MNs in brainstem slices, supporting that baseline ATX activity regulates MN IME. PF-8380-induced alterations were prevented by a small-interfering RNA directed against mRNA for lpa(1). These outcomes support that impact of ATX-originated lysophospholipids on MN IME engages, at least, the G-protein-coupled receptor LPA(1). Interestingly, mRNA(atx) levels increased in the spinal cord of pre-symptomatic (1-2 months old) SOD1-G93A mice, thus preceding MN loss. The rise in transcripts levels also occurred in cultured spinal cord MNs from SOD1-G93A embryos, suggesting that mRNA(atx) upregulation in MNs is an etiopathogenic event in the ALS cell model. Remarkably, chronic administration in the drinking water of the orally bioavailable ATX inhibitor PF-8380 delayed MN loss, motor deterioration and prolonged life span in ALS mice. Treatment also led to a reduction in LPA(1)-immunoreactive patches in transgenic animals mostly in MNs. These outcomes support that neuroprotective effects of interfering with ATX in SOD1-G93A mice rely, at least in part, on LPA(1) knockdown in MNs. Therefore, we propose ATX as a potential target and/or a biomarker in ALS and highlight ATX inhibitors as reasonable tools with therapeutic usefulness for this lethal pathology. ; BFU2015-71422-R (MINECO/FEDER) from Spain's Government; FEDER-UCA18-108475 from the 2014-2020 ERDF Operational Programme and the Department of Economy, Knowledge, Business and University of the Regional Government of Andalusia; LI19/10IN-CO21 from INiBICA to BML and PID2019-110960GB-I00 (MICINN) from Spain's Government to BML and DGF

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.