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The human OPA1delTTAG mutation induces premature age-related systemic neurodegeneration in mouse

Dominant optic atrophy is a rare inherited optic nerve degeneration caused by mutations in the mitochondrial fusion gene OPA1. Recently, the clinical spectrum of dominant optic atrophy has been extended to frequent syndromic forms, exhibiting various degrees of neurological and muscle impairments frequently found in mitochondrial diseases. Although characterized by a specific loss of retinal ganglion cells, the pathophysiology of dominant optic atrophy is still poorly understood. We generated an Opa1 mouse model carrying the recurrent Opa1(delTTAG) mutation, which is found in 30% of all patients with dominant optic atrophy. We show that this mouse displays a multi-systemic poly-degenerative phenotype, with a presentation associating signs of visual failure, deafness, encephalomyopathy, peripheral neuropathy, ataxia and cardiomyopathy. Moreover, we found premature age-related axonal and myelin degenerations, increased autophagy and mitophagy and mitochondrial supercomplex instability preceding degeneration and cell death. Thus, these results support the concept that Opa1 protects against neuronal degeneration and opens new perspectives for the exploration and the treatment of mitochondrial diseases

Effets des ondes électromagnétiques émises par les téléphones cellulaires sur le système nerveux central du rat

MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Immunohistochemistry as a tool for topographial semi-quantification of neurotransmitters in the brain

International audienceImmunohistochemistry is a powerful tool to detect neurotransmitter (NT) presence in different brain structures with a high spatial resolution. However, it is only scarcely used in quantitative approach due to lack of reproducibility and sensitivity. We developed a protocol of NT detection based on immunohistochemistry and image analysis to show that this approach could also be useful to evaluate NT content variations. We focused our study on the GABAergic system in the cerebellum and measured different accurate parameters, namely the optical density (O.D.), the stained area and the number of immunoreactive cells in each cerebellar cell layer. In order to modify the GABA content, we used gamma-vinyl-GABA (GVG), an inhibitor of GABA-transaminase, known to dramatically increase GABA concentration in the central nervous system (CNS) and especially in the cerebellum. We observed a significant increase in the three parameters measured in the molecular and the granular layers of the cerebellum after treatment with GVG, reflecting the well-established increase in GABA content after such a treatment. Therefore, our technical approach allows not only a precise determination of the effects in particular cell layers but also a semi-quantification of GABA content variations. This technique could be suitable for monitoring NT variations following any treatment

Acute exposure to GSM 900-MHz electromagnetic fields induces glial reactivity and biochemical modifications in the rat brain

International audienceThe worldwide proliferation of mobile phones raises the question of the effects of 900-MHz electromagnetic fields (EMF) on the brain. Using a head-only exposure device in the rat, we showed that a 15-min exposure to 900-MHz pulsed microwaves at a high brain-averaged power of 6 W/kg induced a strong glial reaction in the brain. This effect, which suggests neuronal damage, was particularly pronounced in the striatum. Moreover, we observed significant and immediate effects on the K-d and B-max values of N-methyl-D-aspartate (NMDA) and GABA(A) receptors as well as on dopamine transporters. Decrease of the amount of NMDA receptors at the postsynaptic membrane is also reported. Although we showed that the rat general locomotor behavior was not significantly altered on the short term, our results provide the first evidence for rapid cellular and molecular alterations in the rat brain after an acute exposure to high power GSM (Global System for Mobile communication) 900-MHz microwaves

Cellular senescence impact on immune cell fate and function

International audienceCellular senescence occurs not only in cultured fibroblasts, but also in undifferentiated and specialized cells from various tissues of all ages, in vitro and in vivo. Here, we review recent findings on the role of cellular senescence in immune cell fate decisions in macrophage polarization, natural killer cell phenotype, and following T-lymphocyte activation. We also introduce the involvement of the onset of cellular senescence in some immune responses including T-helper lymphocyte-dependent tissue homeostatic functions and T-regulatory cell-dependent suppressive mechanisms. Altogether, these data propose that cellular senescence plays a wide-reaching role as a homeostatic orchestrator

Arthritis sensory and motor scale: predicting functional deficits from the clinical score in collagen-induced arthritis

International audienceBackground: In the collagen-induced arthritis (CIA) mouse model, inflammation readouts are usually quantifiedusing operator-dependent clinical scoring systems, and no systematic relationship with functional deficits has beendetected. In this study, we extensively quantified sensory and motor deficits in CIA mice during natural diseaseprogression and therapeutic treatment. Then, we used these data to build a scale to predict functional deficits onthe basis of the classical clinical score.Methods: Using the CIA mouse model, we longitudinally screened multiple approaches to assess locomotion(open field test, Catwalk™), sensitivity (Von Frey, Hargreaves, static weight-bearing tests), and inflammation (skintemperature), and identified the most accurate tests to correlate sensory and motor deficits with disease severity,measured by clinical score. We then used these tests to characterize functional deficits in control (naïve and miceinjected with complete Freund’s adjuvant) and CIA mice, either untreated or treated with methotrexate to preventfunctional deficits. By mathematical approaches, we finally investigated the relationship between functional deficitsand clinical score.Results: We found that the functional disability scores obtained with the open field, Catwalk™, Hargreaves, and skintemperature tests significantly correlated with the clinical score in CIA mice, either untreated or treated withmethotrexate. Mathematical correlation showed that motor deficits, robustly characterized by two different tests,were twice more responsive than thermal sensitivity deficits.Conclusion: We propose the arthritis sensory and motor (ArthriSM) scale as a new theranostic tool to predictmotor and sensory deficit based on the clinical score, in the experimental mouse model of CIA. This ArthriSM scalemay facilitate the transfer of knowledge between preclinical and clinical studies

Inducible Treg cell populations as cell based-therapy for rheumatoid arthritis

International audienc