Targeting autotaxin impacts disease advance in the SOD1-G93A mouse model of amyotrophic lateral sclerosis

A promising preclinical strategy to identify potential treatments for amyotrophic lateral sclerosis (ALS) involves understanding the factors that control motor neuron (MN) excitability. These factors may be involved in unknown pathogenic pathways and could be useful for designing new interventions to slow disease progression. In this context, the bioactive phospholipid lysophosphatidic acid (LPA) influences MN excitability through the LPA receptor 1 (LPA1). Moreover, LPA1 knockdown has been shown to have neuroprotective effects in transgenic ALS SOD1-G93A mice. Based on these findings, we hypothesized that autotaxin (ATX), the major enzyme responsible for synthesizing LPA, regulates MN excitability and could be a potential target for modulating ALS progression. Our results demonstrate that PF-8380, a specific ATX inhibitor, reduced intrinsic membrane excitability (IME) of hypoglossal MNs in brainstem slices, indicating that baseline ATX activity is involved in regulating MN IME. The effects of PF-8380 were reversed by small-interfering RNA targeting LPA1 mRNA, suggesting that ATX-derived lysophospholipids affect MN IME via LPA1. Notably, mRNA levels of ATX were elevated in the spinal cord of pre-symptomatic (1-2 months old) SOD1-G93A mice, preceding MN loss. This increase in ATX expression was also observed in cultured spinal cord MNs from SOD1-G93A embryos, implying that mRNA upregulation in MNs is an early pathogenic event in ALS. Remarkably, chronic oral administration of the bioavailable ATX inhibitor PF-8380 delayed MN loss, motor decline, and extended lifespan in ALS mice. Treatment also reduced LPA1-immunoreactive patches, particularly in MNs. These findings suggest that the neuroprotective effects of ATX inhibition in SOD1-G93A mice are, at least in part, mediated through LPA1 knockdown in MNs. Based on these results, we propose ATX as a potential therapeutic target and/or biomarker in ALS, and highlight ATX inhibitors as promising tools for treating this devastating disease.