Satoshi Ishii

The developmental process of central nervous system (CNS) myelin sheath formation is characterized by well‐coordinated cellular activities ultimately ensuring rapid and synchronized neural communication. During this process, myelinating CNS cells, namely oligodendrocytes (OLGs), undergo distinct steps of differentiation, whereby the progression of earlier maturation stages of OLGs represents a critical step toward the timely establishment of myelinated axonal circuits. Given the complexity of functional integration, it is not surprising that OLG maturation is controlled by a yet fully to be defined set of both negative and positive modulators. In this context, we provide here first evidence for a role of lysophosphatidic acid (LPA) signaling via the G protein‐coupled receptor LPA 6 as a negative modulatory regulator of myelination‐associated gene expression in OLGs. More specifically, the cell surface accessibility of LPA 6 was found to be restricted to the earlier maturation stages of differentiating OLGs, and OLG maturation was found to occur precociously in Lpar6 knockout mice. To further substantiate these findings, a novel small molecule ligand with selectivity for preferentially LPA 6 and LPA 6 agonist characteristics was functionally characterized in vitro in primary cultures of rat OLGs and in vivo in the developing zebrafish. Utilizing this approach, a negative modulatory role of LPA 6 signaling in OLG maturation could be corroborated. During development, such a functional role of LPA 6 signaling likely serves to ensure timely coordination of circuit formation and myelination. Under pathological conditions as seen in the major human demyelinating disease multiple sclerosis (MS), however, persistent LPA 6 expression and signaling in OLGs can be seen as an inhibitor of myelin repair. Thus, it is of interest that LPA 6 protein levels appear elevated in MS brain samples, thereby suggesting that LPA 6 signaling may represent a potential new druggable pathway suitable to promote myelin repair in MS. image

In human autosomal recessive woolly hair/hypotrichosis (ARWH/HT), many mutations have been identified in a gene encoding LPA6, a G protein-coupled receptor (GPCR) for lysophosphatidic acid (LPA). However, information regarding the effects of such mutations on receptor function is limited. In this study, we examined functional impacts of selected amino acid changes in LPA6 identified in ARWH/HT patients. In our exogenous expression experiments, all mutants except S3T failed to respond to LPA, indicating that they are loss-of-function mutants. Among the nine mutants, five (D63V, G146R, N246D, L277P and C278Y) displayed impaired expression at the cell surface because of endoplasmic reticulum (ER) retention, indicating that these mutants are trafficking-defective, as reported in other disease-associated GPCRs. Notably, alkyl-OMPT, a potent synthetic agonist for LPA6 restored the defective cell surface expression of two of the ER-retained mutants, D63V and N246D, possibly by its chaperoning function that allows them to escape intracellular retention as well as proteasomal degradation. Furthermore, the alkyl-OMPT-rescued N246D mutant was shown be functional. Our findings encourage future application of pharmacoperone therapy for ARWH/HT patients with specific LPA6 mutations.