Aims: Alterations in excitability represent an early hallmark in Amyotrophic Lateral Sclerosis (ALS). Therefore, deciphering the factors that impact motor neuron (MN) excitability offers an opportunity to uncover further aetiopathogenic mechanisms, neuroprotective agents, therapeutic targets, and/or biomarkers in ALS. Here, we hypothesised that the lipokine lysophosphatidic acid (lpa) regulates MN excitability via the G-proteincoupled receptor lpa 1 . Then, modulating lpa 1 -mediated signalling might affect disease progression in the ALS SOD1-G93A mouse model. Methods:The influence of lpa-lpa 1 signalling on the electrical properties, Ca 2+ dynamic and survival of MNs was tested in vitro. Expression of lpa 1 in cultured MNs and in the spinal cord of SOD1-G93A mice was analysed. ALS mice were chronically treated with a small-interfering RNA against lpa 1 (siRNA lpa1 ) or with the lpa 1 inhibitor AM095. Motor skills, MN loss, and lifespan were evaluated.Results: AM095 reduced MN excitability. Conversely, exogenous lpa increased MN excitability by modulating task1 'leak' potassium channels downstream of lpa 1 . Lpa-lpa 1 signalling evoked an excitotoxic response in MNs via voltage-sensitive calcium channels.Cultured SOD1-G93A MNs displayed lpa 1 upregulation and heightened vulnerability to lpa. In transgenic mice, lpa 1 was upregulated mostly in spinal cord MNs before cell loss. Chronic administration of either siRNA lpa1 or AM095 reduced lpa 1 expression at least in MNs, delayed MN death, improved motor skills, and prolonged life expectancy of ALS mice.Conclusions: These results suggest that stressed lpa-lpa 1 signalling contributes to MN degeneration in SOD1-G93A mice. Consequently, disrupting lpa 1 slows down disease progression. This highlights LPA 1 signalling as a potential target and/or biomarker in ALS.
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.
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