Interfering with lysophosphatidic acid receptor edg2/lpa 1 signalling slows down disease progression in SOD1‐G93A transgenic mice
| Autor: | Bernardo Moreno-López, Ángela Gento-Caro, Victoria García-Morales, Guillermo Rodríguez-Bey, Esther Vilches-Herrando, Federico Portillo, David González-Forero |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Histology Excitotoxicity Biology medicine.disease_cause Neuroprotection Pathology and Forensic Medicine 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation Physiology (medical) Lysophosphatidic acid medicine Voltage-dependent calcium channel Neurodegeneration Motor neuron medicine.disease Cell biology 030104 developmental biology medicine.anatomical_structure Neurology chemistry Neurology (clinical) 030217 neurology & neurosurgery |
| Zdroj: | Neuropathology and Applied Neurobiology. 47:1004-1018 |
| ISSN: | 1365-2990 0305-1846 |
| Popis: | 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 hypothesized 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. |
| Databáze: | OpenAIRE |
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