Dual role of Lysophosphatidic Acid Receptor 2 (LPA) in amyotrophic lateral sclerosis
Puigdomenech Poch, Maria (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Martínez Muriana, Anna (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Andrés-Benito, P (Institut d'Investigació Biomèdica de Bellvitge)
Ferrer, Isidro (Institut d'Investigació Biomèdica de Bellvitge)
Chun, Jerold (Sanford Burnham Prebys Medical Discovery Institute)
López Vales, Rubén (Universitat Autònoma de Barcelona. Institut de Neurociències)

Date:	2021
Abstract:	Lysophosphatidic acid (LPA) is a pleiotropic extracellular lipid mediator with many physiological functions that signal through six known G protein-coupled receptors (LPA). In the central nervous system (CNS), LPA mediates a wide range of effects including neural progenitor cell physiology, neuronal cell death, axonal retraction, and inflammation. Since inflammation is a hallmark of most neurological conditions, we hypothesized that LPA could be involved in the physiopathology of amyotrophic lateral sclerosis (ALS). We found that LPA RNA was upregulated in post-mortem spinal cord samples of ALS patients and in the sciatic nerve and skeletal muscle of SOD1 G93A mouse, the most widely used ALS mouse model. To assess the contribution of LPA to ALS, we generated a SOD1 G93A mouse that was deficient in Lpar2. This animal revealed that LPA signaling accelerates disease onset and neurological decline but, unexpectedly, extended the lifespan. To gain insights into the early harmful actions of LPA in ALS, we studied the effects of this receptor in the spinal cord, peripheral nerve, and skeletal muscle of ALS mice. We found that LPA gene deletion increased microglial activation but did not contribute to motoneuron death, astrogliosis, degeneration, and demyelination of motor axons. However, we observed that Lpar2 deficiency protected against muscle atrophy. Moreover, we also found the deletion of Lpar2 reduced the invasion of macrophages into the skeletal muscle of SOD1 G93A mice, linking LPA signaling with muscle inflammation and atrophy in ALS. Overall, these results suggest for the first time that LPA contributes to ALS, and its genetic deletion results in protective actions at the early stages of the disease but shortens survival thereafter.
Grants:	Ministerio de Economía y Competitividad SAF2016-79774-R
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Amyotrophic lateral sclerosis ; LPA2 ; Lysophosphatidic acid ; Lysophosphatidic acid receptor ; Inflammation ; Motoneuron ; Muscle atrophy
Published in:	Frontiers in cellular neuroscience, Vol. 15 (March 2021) , art. 600872, ISSN 1662-5102

DOI: 10.3389/fncel.2021.600872
PMID: 33841099

14 p, 6.5 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Neurociències (INc)
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