Peripheral axonal ensheathment is regulated by RalA GTPase and the exocyst complex

Funding This work was supported by H2020 Marie Skłodowska-Curie Actions [H2020- GA661543-Neuronal Trafficking to R.O.T.], Fundo Regional para a Ciência e Tecnologia [IF/00392/2013/CP1192/CT0002 to R.O.T.] and iNOVA4Health (UID/Multi/04462/2013) (co-funded by FCT-FEDER-PT2020).Axon ensheathment is fundamental for fast impulse conduction and the normal physiological functioning of the nervous system. Defects in axonal insulation lead to debilitating conditions, but, despite its importance, the molecular players responsible are poorly defined. Here, we identify RalA GTPase as a key player in axon ensheathment in Drosophila larval peripheral nerves. We demonstrate through genetic analysis that RalA action through the exocyst complex is required in wrapping glial cells to regulate their growth and development. We suggest that the RalA-exocyst pathway controls the targeting of secretory vesicles for membrane growth or for the secretion of a wrapping glia-derived factor that itself regulates growth. In summary, our findings provide a new molecular understanding of the process by which axons are ensheathed in vivo, a process that is crucial for normal neuronal function.publishersversionpublishe

Leukocyte Imbalances in Mucopolysaccharidoses Patients

(This article belongs to the Special Issue Inherited Metabolic Disorders: From Bench to Bedside)Mucopolysaccharidoses (MPSs) are rare inherited lysosomal storage diseases (LSDs) caused by deficient activity in one of the enzymes responsible for glycosaminoglycans lysosomal degradation. MPS II is caused by pathogenic mutations in the IDS gene, leading to deficient activity of the enzyme iduronate-2-sulfatase, which causes dermatan and heparan sulfate storage in the lysosomes. In MPS VI, there is dermatan sulfate lysosomal accumulation due to pathogenic mutations in the ARSB gene, leading to arylsulfatase B deficiency. Alterations in the immune system of MPS mouse models have already been described, but data concerning MPSs patients is still scarce. Herein, we study different leukocyte populations in MPS II and VI disease patients. MPS VI, but not MPS II patients, have a decrease percentage of natural killer (NK) cells and monocytes when compared with controls. No alterations were identified in the percentage of T, invariant NKT, and B cells in both groups of MPS disease patients. However, we discovered alterations in the naïve versus memory status of both helper and cytotoxic T cells in MPS VI disease patients compared to control group. Indeed, MPS VI disease patients have a higher frequency of naïve T cells and, consequently, lower memory T cell frequency than control subjects. Altogether, these results reveal MPS VI disease-specific alterations in some leukocyte populations, suggesting that the type of substrate accumulated and/or enzyme deficiency in the lysosome may have a particular effect on the normal cellular composition of the immune system.This work was funded by National Funds through FCT—Fundação para a Ciência e a Tecnologia, I.P., under the project UIDB/04293/2020.info:eu-repo/semantics/publishedVersio

StressMatic: a novel automated system to induce depressive- and anxiety-like phenotype in rats

Major depressive disorder (MDD) is a multidimensional psychiatric disorder that is estimated to affect around 350 million people worldwide. Generating valid and effective animal models of depression is critical and has been challenging for neuroscience researchers. For preclinical studies, models based on stress exposure, such as unpredictable chronic mild stress (uCMS), are amongst the most reliable and used, despite presenting concerns related to the standardization of protocols and time consumption for operators. To overcome these issues, we developed an automated system to expose rodents to a standard uCMS protocol. Here, we compared manual (uCMS) and automated (auCMS) stress-exposure protocols. The data shows that the impact of the uCMS exposure by both methods was similar in terms of behavioral (cognition, mood, and anxiety) and physiological (cell proliferation and endocrine variations) measurements. Given the advantages of time and standardization, this automated method represents a step forward in this field of preclinical research.This research was funded by Bn’ML—Behavioral and Molecular Lab and by the National Strategic Reference Framework (QREN). L.P. and F.V. were funded by the Portuguese Foundation for Science and Technology (FCT) (2020.02855.CEECIND to L.P.; SFRH/BD/131545/2017 to F.V.). This work was funded by the Nature Research Award for Driving Global Impact—2019 Brain Sciences (to L.P.). J.F.O. received funding from FCT (projects PTDC/MED-NEU/31417/2017) and POCI-01-0145-FEDER-016818; grants from Bial Foundation (037/18) and ”la Caixa” Foundation (LCF/PR/HR21/52410024) to J.F.O. A.J.R. was funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 101003187), by “la Caixa” Foundation (ID 100010434), under the agreement LCF/PR/HR20/52400020, by FCT under the scope of the project PTDC/MED-NEU/4804/2020 (ENDOPIO). This work was also co-funded by the Life and Health Sciences Research Institute (ICVS); funded by ICVS Scientific Microscopy Platform, member of the national infrastructure PPBI—Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122); and funded by National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020