Peroxisome deficiency but not the defect in ether lipid synthesis causes activation of the innate immune system and axonal loss in the central nervous system

Background: Mice with peroxisome deficiency in neural cells (Nestin-Pex5 −/− ) develop a neurodegenerative phenotype leading to motor and cognitive disabilities and early death. Major pathologies at the end stage of disease include severe demyelination, axonal degeneration and neuroinflammation. We now investigated the onset and progression of these pathological processes, and their potential interrelationship. In addition, the putative role of oxidative stress, the impact of plasmalogen depletion on the neurodegenerative phenotype, and the consequences of peroxisome elimination in the postnatal period were studied. Methods: Immunohistochemistry in association with gene expression analysis was performed on Nestin-Pex5 −/− mice to document demyelination, axonal damage and neuroinflammation. Also Gnpat −/− mice, with selective plasmalogen deficiency and CMV-Tx-Pex5 −/− mice, with tamoxifen induced generalized loss of peroxisomes were analysed. Results: Activation of the innate immune system is a very early event in the pathological process in Nestin-Pex5 −/− mice which evolves in chronic neuroinflammation. The complement factor C1q, one of the earliest up regulated transcripts, was expressed on neurons and oligodendrocytes but not on microglia. Transcripts of other pro- and anti-inflammatory genes and markers of phagocytotic activity were already significantly induced before detecting pathologies with immunofluorescent staining. Demyelination, macrophage activity and axonal loss co-occurred throughout the brain. As in patients with mild peroxisome biogenesis disorders who develop regressive changes, demyelination in cerebellum and brain stem preceded major myelin loss in corpus callosum of both Nestin-Pex5 −/− and CMV-Tx-Pex5 −/− mice. These lesions were not accompanied by generalized oxidative stress throughout the brain. Although Gnpat −/− mice displayed dysmyelination and Purkinje cell axon damage in cerebellum, confirming previous observations, no signs of inflammation or demyelination aggravating with age were observed. Conclusions: Peroxisome inactivity triggers a fast neuroinflammatory reaction, which is not solely due to the depletion of plasmalogens. In association with myelin abnormalities this causes axon damage and loss

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

Peroxisomal alterations in Alzheimer’s disease

In Alzheimer’s disease (AD), lipid alterations are present early during disease progression. As some of these alterations point towards a peroxisomal dysfunction, we investigated peroxisomes in human postmortem brains obtained from the cohort-based, longitudinal Vienna-Transdanube Aging (VITA) study. Based on the neuropathological Braak staging for AD on one hemisphere, the patients were grouped into three cohorts of increasing severity (stages I–II, III–IV, and V–VI, respectively). Lipid analyses of cortical regions from the other hemisphere revealed accumulation of C22:0 and very long-chain fatty acids (VLCFA, C24:0 and C26:0), all substrates for peroxisomal β-oxidation, in cases with stages V–VI pathology compared with those modestly affected (stages I–II). Conversely, the level of plasmalogens, which need intact peroxisomes for their biosynthesis, was decreased in severely affected tissues, in agreement with a peroxisomal dysfunction. In addition, the peroxisomal volume density was increased in the soma of neurons in gyrus frontalis at advanced AD stages. Confocal laser microscopy demonstrated a loss of peroxisomes in neuronal processes with abnormally phosphorylated tau protein, implicating impaired trafficking as the cause of altered peroxisomal distribution. Besides the original Braak staging, the study design allowed a direct correlation between the biochemical findings and the amount of neurofibrillary tangles (NFT) and neuritic plaques, quantified in adjacent tissue sections. Interestingly, the decrease in plasmalogens and the increase in VLCFA and peroxisomal volume density in neuronal somata all showed a stronger association with NFT than with neuritic plaques. These results indicate substantial peroxisome-related alterations in AD, which may contribute to the progression of AD pathology