Interfering with lysophosphatidic acid receptor edg2/lpa1 signalling slows down disease progression in SOD1‐G93A transgenic mice

• Published in: Neuropathology and applied neurobiology Vol. 47; no. 7; pp. 1004 - 1018
• Main Authors: Gento‐Caro, Ángela, Vilches‐Herrando, Esther, García‐Morales, Victoria, Portillo, Federico, Rodríguez‐Bey, Guillermo, González‐Forero, David, Moreno‐López, Bernardo
• Format: Journal Article
• Language: English
• Published: Oxford Wiley Subscription Services, Inc 01-12-2021
• Subjects: Amyotrophic lateral sclerosis; background potassium channels; Biomarkers; Calcium channels; Calcium channels (voltage-gated); Degeneration; Electrical properties; Excitability; Excitotoxicity; intrinsic membrane excitability; Life span; lpa1/edg2/vzg1; Lysophosphatidic acid; Motor ability; Motor skill; neurodegeneration; Neuroprotection; Neuroprotective agents; Potassium channels; SOD1‐G93A model; Spinal cord; Superoxide dismutase; Transgenic animals; Transgenic mice
• ISSN: 0305-1846; 1365-2990
• DOI: 10.1111/nan.12699

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‐protein‐coupled receptor lpa1. Then, modulating lpa1‐mediated signalling might affect disease progression in the ALS SOD1‐G93A mouse model.
Methods
The influence of lpa‐lpa1 signalling on the electrical properties, Ca2+ dynamic and survival of MNs was tested in vitro. Expression of lpa1 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 lpa1 (siRNAlpa1) or with the lpa1 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 lpa1. Lpa‐lpa1 signalling evoked an excitotoxic response in MNs via voltage‐sensitive calcium channels. Cultured SOD1‐G93A MNs displayed lpa1 upregulation and heightened vulnerability to lpa. In transgenic mice, lpa1 was upregulated mostly in spinal cord MNs before cell loss. Chronic administration of either siRNAlpa1 or AM095 reduced lpa1 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‐lpa1 signalling contributes to MN degeneration in SOD1‐G93A mice. Consequently, disrupting lpa1 slows down disease progression. This highlights LPA1 signalling as a potential target and/or biomarker in ALS.
Ángela Gento‐Caro, Bernardo Moreno‐López, and co‐workers reveal a mechanism of action by which the lipokine lysophosphatidic acid (LPA) evokes excitotoxic motor neuron degeneration. Interfering with its main receptor LPA1 is neuroprotective in an ALS mouse model.