Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination

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.We thank Paula Sampaio for microscopy support, Paula Magalhdes for genotyping, and Isabel Carvalho, Sofia Lamas, and Fatima Martins for excellent animal care. We are grateful to P. Brophy (University of Edinburgh) for the DRP2 antibody and to M. Baes (K.U. Leuven) for providing the Gnpat mouse strain. This work was funded by the Research Foundation of the European Leukodystrophy Association (ELA 2008-009C4, ELA 2010-042C5), by FEDER Funds through the Operational Competitiveness Program - COMPETE, and by national funds through the FCT - Fundacao para a Ciencia e a Tecnologia under the project FCOMP-01-0124-FEDER-015970 (PTDS/SAU-ORG/112406/2009). P. Brites is an FCT Investigator, and T. Ferreira da Silva was supported by the FCT (SFRH/BD/88160/2012)

RhoA Regulates Peroxisome Association to Microtubules and the Actin Cytoskeleton

Peer reviewe

Gender and age differences in the recurrence of sickness absence due to common mental disorders: a longitudinal study

Background: Common mental disorders (CMDs) are an important cause of sickness absence and long-term work disability. Although CMDs are known to have high recurrence rates, little is known about the recurrence of sickness absence due to CMDs. The aim of this study was to investigate the recurrence of sickness absence due to CMDs, including distress, adjustment disorders, depressive disorders and anxiety disorders, according to age, in male and female employees in the Netherlands. Methods: Data on sickness absence episodes due to CMDs were obtained for 137,172 employees working in the Dutch Post and Telecommunication companies between 2001 and 2007. The incidence density (ID) and recurrence density (RD) of sickness absence due to CMDs was calculated per 1000 person-years in men and women in the age-groups of < 35 years, 35-44 years, 45-54 years, and >= 55 years. Results: The ID of one episode of CMDs sickness absence was 25.0 per 1000 person-years, and the RD was 76.7 per 1000 person-years. Sickness absence due to psychiatric disorders (anxiety and depression) does not have a higher recurrence density of sickness absence due to any CMDs as compared to stress-related disorders (distress and adjustment disorders): 81.6 versus 76.0 per 1000 person-years. The ID of sickness absence due to CMDs was higher in women than in men, but the RD was similar. Recurrences were more frequent in women < 35 years and in women between 35 and 44 years of age. We observed no differences between age groups in men. Recurrences among employees with recurrent episodes occurred within 3 years in 90% of cases and the median time-to-onset of recurrence was 11 (10-13) months in men and 10 (9-12) months in women. Conclusions: Employees who have been absent from work due to CMDs are at increased risk of recurrent sickness absence due to CMDs and should be monitored after they return to work. The RD was similar in men and in women. In women < 45 years the RD was higher than in women >= 45 years. In men no age differences were observed

Review

+ mode

Defects in myelination, paranode organization and Purkinje cell innervation in the ether lipid-deficient mouse cerebellum

Ether lipids (ELs), particularly plasmalogens, are essential constituents of the mammalian central nervous system. The physiological role of ELs, in vivo, however is still enigmatic. In the present study, we characterized a mouse model carrying a targeted deletion of the peroxisomal dihydroxyacetonephosphate acyltransferase gene that results in the complete lack of ELs. Investigating the cerebellum of these mice, we observed: (i) defects in foliation patterning and delay in precursor granule cell migration, (ii) defects in myelination and concomitant reduction in the level of myelin basic protein, (iii) disturbances in paranode organization by extending the Caspr distribution and disrupting axo-glial septate-like junctions, (iv) impaired innervation of Purkinje cells by both parallel fibers and climbing fibers and (v) formation of axon swellings by the accumulation of inositol-tris-phosphate receptor 1 containing smooth ER-like tubuli. Functionally, conduction velocity of myelinated axons in the corpus callosum was significantly reduced. Most of these phenotypes were already apparent at P20 but still persisted in 1-year-old animals. In summary, these data show that EL deficiency results in severe developmental and lasting structural alterations at the cellular and network level of the cerebellum, and reveal an important role of ELs for proper brain function. Common molecular mechanisms that may underlie these phenotypes are discussed

Ether lipid biosynthesis: isolation and molecular characterization of human dihydroxyacetonephosphate acyltransferase

AbstractIn this paper we describe isolation and molecular characterization of human dihydroxyacetonephosphate acyltransferase (DAP-AT). The enzyme was extracted from rabbit Harderian gland peroxisomes and isolated as a trimeric complex by sucrose density gradient centrifugation. From peptide sequences matching EST-clones were obtained which allowed cloning and sequencing of the cDNA from a human cDNA library. The nucleotide-derived amino acid sequence revealed a protein consisting of 680 amino acid residues of molecular mass 77 187 containing a C-terminal type 1 peroxisomal targeting signal. Monospecific antibodies raised against this polypeptide efficiently immunoprecipitated DAP-AT activity from solubilized peroxisomal preparations, thus demonstrating that the cloned cDNA codes for DAP-AT