Patients with the peroxisomal disorder rhizomelic chrondrodysplasia punctata (RCDP) present with low muscle tone, cataracts, skeletal abnormalities, impaired motor function, and intellectual disability. Development of RCDP is associated with reduced levels of plasmalogens, neuronal-enriched ether-phospholipids that mediate membrane properties. Using murine models of RCDP, Pedro Brites and colleagues at the Instituto de Biologia Molecular e Celular specifically investigated the effects plasmalogen insufficiency on the peripheral nervous system. Schwann cell development and function were impaired in mutant animals, resulting in defective myelination and myelin structures. Plasmalogen reduction was associated with defective AKT kinase signaling, which enhanced activation of glycogen synthase kinase 3β (GSK3β), a regulator of neuronal development. Treatment of RCDP mice with pharmacological inhibitors of GSK3β ameliorated plasmalogen deficiency-associated defects. This study reveals that reduced plasmalogen in the peripheral nervous system affects Schwann cells and neuronal myelination. Furthermore, this work suggests that AKT-mediated signaling should be further investigated as a therapeutic target. The accompanying electron micrograph depicts a severely demyelinated axon in the sciatic nerve of a RCDP mouse and illustrates that mutant Schwann cells produce and extend processes to engulf demyelinated axons, and other myelinated fibers in failed attempts to protect axons and remyelinate the nerve.
Rhizomelic chondrodysplasia punctata (RCDP) is a developmental disorder characterized by hypotonia, cataracts, abnormal ossification, impaired motor development, and intellectual disability. The underlying etiology of RCDP is a deficiency in the biosynthesis of ether phospholipids, of which plasmalogens are the most abundant form in nervous tissue and myelin; however, the role of plasmalogens in the peripheral nervous system is poorly defined. Here, we used mouse models of RCDP and analyzed the consequence of plasmalogen deficiency in peripheral nerves. We determined that plasmalogens are crucial for Schwann cell development and differentiation and that plasmalogen defects impaired radial sorting, myelination, and myelin structure. Plasmalogen insufficiency resulted in defective protein kinase B (AKT) phosphorylation and subsequent signaling, causing overt activation of glycogen synthase kinase 3β (GSK3β) in nerves of mutant mice. Treatment with GSK3β inhibitors, lithium, or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) restored Schwann cell defects, effectively bypassing plasmalogen deficiency. Our results demonstrate the requirement of plasmalogens for the correct and timely differentiation of Schwann cells and for the process of myelination. In addition, these studies identify a mechanism by which the lack of a membrane phospholipid causes neuropathology, implicating plasmalogens as regulators of membrane and cell signaling.
Tiago Ferreira da Silva, Jessica Eira, André T. Lopes, Ana R. Malheiro, Vera Sousa, Adrienne Luoma, Robin L. Avila, Ronald J.A. Wanders, Wilhelm W. Just, Daniel A. Kirschner, Mónica M. Sousa, Pedro Brites