Pleotropic Roles of Autotaxin in the Nervous System Present Opportunities for the Development of Novel Therapeutics for Neurological Diseases

• Published in: Molecular neurobiology Vol. 57; no. 1; pp. 372 - 392
• Main Authors: Herr, Deron R., Chew, Wee Siong, Satish, R. L., Ong, Wei-Yi
• Format: Journal Article
• Language: English
• Published: New York Springer US 2020; Springer Nature B.V
• Subjects: Alcohols; Biological effects; Biomedical and Life Sciences; Biomedicine; Brain; Brain damage; Cell Biology; Central nervous system; Cerebrospinal fluid; Clinical trials; Cytoskeleton; Drug development; Edema; Enzymatic activity; G protein-coupled receptors; Glioblastoma; Hemorrhage; Hepatic encephalopathy; Hydrocephalus; Inflammation; Lysophosphatidic acid; Medical treatment; Mental depression; Mental disorders; Metabolic disorders; Metabolic syndrome; Multiple sclerosis; Nervous system; Neurobiology; Neurology; Neurosciences; Peripheral nerves; Peripheral neuropathy; Schizophrenia; Traumatic brain injury; Inflammatory neuropathic pain; Multiple sclerosis; Lysophospholipase D; Traumatic brain injury; Alzheimer’s disease; Hepatic encephalopathy induced cerebral edema; HIV-induced brain injury; Schizophrenia; Peripheral nerve injury; Pruritus; Glioblastoma multiforme; Hemorrhagic hydrocephalus; Major depressive disorder; Alcohol-induced brain damage; Metabolic syndrome-induced brain damage; Autotaxin; Stress-induced psychiatric disorder; Macular edema
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-019-01719-1

Autotaxin (ATX) is a soluble extracellular enzyme that is abundant in mammalian plasma and cerebrospinal fluid (CSF). It has two known enzymatic activities, acting as both a phosphodiesterase and a phospholipase. The majority of its biological effects have been associated with its ability to liberate lysophosphatidic acid (LPA) from its substrate, lysophosphatidylcholine (LPC). LPA has diverse pleiotropic effects in the central nervous system (CNS) and other tissues via the activation of a family of six cognate G protein-coupled receptors. These LPA receptors (LPARs) are expressed in some combination in all known cell types in the CNS where they mediate such fundamental cellular processes as proliferation, differentiation, migration, chronic inflammation, and cytoskeletal organization. As a result, dysregulation of LPA content may contribute to many CNS and PNS disorders such as chronic inflammatory or neuropathic pain, glioblastoma multiforme (GBM), hemorrhagic hydrocephalus, schizophrenia, multiple sclerosis, Alzheimer’s disease, metabolic syndrome-induced brain damage, traumatic brain injury, hepatic encephalopathy-induced cerebral edema, macular edema, major depressive disorder, stress-induced psychiatric disorder, alcohol-induced brain damage, HIV-induced brain injury, pruritus, and peripheral nerve injury. ATX activity is now known to be the primary biological source of this bioactive signaling lipid, and as such, represents a potentially high-value drug target. There is currently one ATX inhibitor entering phase III clinical trials, with several additional preclinical compounds under investigation. This review discusses the physiological and pathological significance of the ATX-LPA-LPA receptor signaling axis and summarizes the evidence for targeting this pathway for the treatment of CNS diseases.