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A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS
Published on: October 6, 2015
Targeting autotaxin impacts disease advance in the SOD1-G93A mouse model of amyotrophic lateral sclerosis
Ángela Gento-Caro1, Esther Vilches-Herrando1, Federico Portillo1
1GRUpo de NEuroDEgeneración y NeurorREparación (GRUNEDERE), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz-Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain.
Abstract:
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 (LPA1 ). Furthermore, LPA1 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 lpa1 . These outcomes support that impact of ATX-originated lysophospholipids on MN IME engages, at least, the G-protein-coupled receptor LPA1 . Interestingly, mRNAatx 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 mRNAatx 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 LPA1 -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 LPA1 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.
Insights
Autotaxin (ATX) inhibition reduces motor neuron excitability and delays disease progression in preclinical models of amyotrophic lateral sclerosis (ALS). Targeting ATX may offer a novel therapeutic strategy for ALS by modulating lysophosphatidic acid receptor 1 (LPA1) signaling.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron (MN) loss.
- Identifying factors controlling MN excitability is crucial for developing effective ALS treatments.
- Lysophosphatidic acid (LPA) signaling, particularly through LPA receptor 1 (LPA1), influences MN excitability and has shown neuroprotective effects in ALS models.
Purpose of the Study:
- To investigate the role of autotaxin (ATX), a key enzyme in LPA synthesis, in regulating MN excitability and ALS pathogenesis.
- To evaluate the therapeutic potential of ATX inhibition in a preclinical model of ALS.
Main Methods:
- Utilized brainstem slices from mice to assess the effect of the ATX inhibitor PF-8380 on hypoglossal MN intrinsic membrane excitability (IME).
- Employed small interfering RNA (siRNA) to investigate the involvement of LPA1 in ATX inhibitor-mediated effects.
- Measured mRNA levels of ATX in the spinal cords of pre-symptomatic SOD1-G93A mice and cultured MNs.
- Administered PF-8380 orally to SOD1-G93A mice to assess its impact on disease progression, MN loss, and lifespan.
Main Results:
- The ATX inhibitor PF-8380 reduced MN intrinsic membrane excitability (IME), an effect dependent on LPA1.
- mRNA levels of ATX were elevated in the spinal cords of pre-symptomatic SOD1-G93A mice and in cultured MNs, suggesting an early pathogenic role.
- Chronic oral administration of PF-8380 delayed motor deficits, reduced MN loss, and extended lifespan in SOD1-G93A mice.
- PF-8380 treatment decreased LPA1 expression in MNs of treated ALS mice.
Conclusions:
- Autotaxin (ATX) activity regulates motor neuron excitability, at least partly through the LPA1 receptor.
- Increased ATX expression is an early event in the SOD1-G93A mouse model of ALS.
- Inhibiting ATX with PF-8380 demonstrates significant neuroprotective effects and therapeutic potential in preclinical ALS models.
- ATX represents a promising therapeutic target and potential biomarker for amyotrophic lateral sclerosis.
