Chapter five - Biological Effects of Lysophosphatidic Acid in the Nervous System
Introduction
Lipids and their derivatives are essential macromolecules that used to be merely seen as suppliers of energy and as structural cell membrane support. Based on homology of their structure, lipids can be categorized into several groups including phospholipids. There are two main types of phospholipids, glycerophospholipids, which are derived from glycerol, and sphingolipids, which are derived from sphingosine. Aside from their energy and structural functions, a few members of the lipid family are bioactive and induce specific biological effects in various cell types through binding to their specific membrane receptors.
Lysophosphatidic acid (LPA) is a glycerophospholipid that regulates a broad range of cellular responses, including cell growth, migration, and morphology, and it has been shown to play a major role in development. LPA is also an inflammatory and wound-healing mediator that is released from activated platelets and other players in the inflammatory process, including the production of various proinflammatory cytokines. LPA and its receptors are found in the central nervous system (CNS), and LPA has been shown to play a role in CNS development and pathology. This review aims at describing the current knowledge on the effects of LPA in the nervous system, during development, adulthood, and various neuropathologies.
Section snippets
LPA metabolism and catabolism
LPA is not a single molecular entity but a collection of structural analogs with a single functional glycerol alcohol phosphate moiety esterified to a variety of fatty acyl hydrocarbons of varied lengths and degrees of saturation. Detectable levels of LPA have been found in various body fluids, including serum, plasma, saliva, follicular fluid, inflammatory fluids, some malignant effusions, and cerebrospinal fluid (reviewed in Aoki et al., 2008). A broad range of cell types are known to produce
LPA Receptor Expression in the Developing and Adult Nervous System
Various studies have informed on the pattern of expression of LPA receptors in the nervous system and globally indicate that LPA receptors are mainly expressed during development and decrease in adulthood. An elegant study by Ohuchi et al. (2008) described the expression pattern of LPA1–5 by whole-mount in situ hybridization in mouse embryos, confirming and further characterizing the expression profile of LPA receptors in the embryonic and postnatal mouse brain (Ohuchi et al., 2008). These
Neural stem/progenitor cells and neuroblasts
Neural stem cells can differentiate into either neural or neuronal progenitor cells. The neural progenitors are themselves able to differentiate into neurons, astrocytes, and oligodendrocytes while the neuronal progenitor cells, or neuroblasts, can only differentiate into neurons. In the CNS, NS/PCs are found in areas of neurogenesis during development (such as the ventricular zone) as well as in adulthood (such as the subventricular zone, the hippocampus, and potentially the spinal cord). LPA
Development
Atx is found in the floor plate and in the neural tube and then expressed during embryonic development and throughout postnatal life in the spinal cord, cerebellum, optic nerve, and the subventricular zone (Savaskan et al., 2007). Further, the Atx(−/−) in mice is lethal due to the impairment of blood vessel and neural tube formation, while deletion of Atx in mice embryo is accompanied with perturbations in the closure of the neural tube closure and with aberrant neurite outgrowth (Fotopoulou et
Therapeutic Intervention
It is clear from the forgoing review of the literature that the LPA signaling system is quite extensive in the nervous system. LPA itself, its receptors, and the biosynthetic pathways for LPA generation are all present in important areas of the CNS including the hippocampus, subventricular zone, and DRG, and LPA receptors are expressed by all relevant cell types in the central and peripheral nervous systems. LPA is an important growth factor for CNS development, as its absence in the Atx
Concluding Remarks
As described in this review, LPA induces complex effects on all cell types of the nervous system. Not surprisingly, such pleiotropic effects are observed in development as well as in the adult. Studies also indicate important roles of LPA in the nervous system pathology. Development of new tools to access its signaling will undoubtedly give new insight into LPA's mechanisms of actions and provide novel potential therapeutical avenues.
Acknowledgments
This project is proudly supported by the Transport Accident Commission (A. P.). A. P. received a National Health and Medical Research Council Career Development Award. F. F. received an Australian Development Scholarships (ADS) by the Australian government (AusAID).
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