Publicaciones por año
Publicaciones del Departamento de Histología y Embriología
Neuroprotective effects of the mitochondria-targeted antioxidant MitoQ in a model of inherited amyotrophic lateral sclerosis
Free Radic Biol Med 2014 70:204-13
Ernesto Miquel 1 , Adriana Cassina 2 , Laura Martínez-Palma 1 , José M Souza 2 , Carmen Bolatto 1 , Sebastián Rodríguez-Bottero 1 , Angela Logan 3 , Robin A J Smith 4 , Michael P Murphy 3 , Luis Barbeito 5 , Rafael Radi 2 , Patricia Cassina 6
1 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay. 2 Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay; Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay. 3 Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, UK. 4 Department of Chemistry, University of Otago, Dunedin 9054, New Zealand. 5 Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay. 6 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay; Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay
DOI: 10.1016/j.freeradbiomed.2014.02.019
PMID: 24582549
Pubmed: https://pubmed.ncbi.nlm.nih.gov/24582549
Texto completo: https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(14)00096-3
Abstract:
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motor neuron degeneration that ultimately results in progressive paralysis and death. Growing evidence indicates that mitochondrial dysfunction and oxidative stress contribute to motor neuron degeneration in ALS. To further explore the hypothesis that mitochondrial dysfunction and nitroxidative stress contribute to disease pathogenesis at the in vivo level, we assessed whether the mitochondria-targeted antioxidant [10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl]triphenylphosphonium methane sulfonate (MitoQ) can modify disease progression in the SOD1(G93A) mouse model of ALS. To do this, we administered MitoQ (500 µM) in the drinking water of SOD1(G93A) mice from a time when early symptoms of neurodegeneration become evident at 90 days of age until death. This regime is a clinically plausible scenario and could be more easily translated to patients as this corresponds to initiating treatment of patients after they are first diagnosed with ALS. MitoQ was detected in all tested tissues by liquid chromatography/mass spectrometry after 20 days of administration. MitoQ treatment slowed the decline of mitochondrial function, in both the spinal cord and the quadriceps muscle, as measured by high-resolution respirometry. Importantly, nitroxidative markers and pathological signs in the spinal cord of MitoQ-treated animals were markedly reduced and neuromuscular junctions were recovered associated with a significant increase in hindlimb strength. Finally, MitoQ treatment significantly prolonged the life span of SOD1(G93A) mice. Our results support a role for mitochondrial nitroxidative damage and dysfunction in the pathogenesis of ALS and suggest that mitochondria-targeted antioxidants may be of pharmacological use for ALS treatment.
Pharmacological study of the one spike spherical neuron phenotype in Gymnotus omarorum
Neuroscience 2014 258:347-54
J Nogueira 1, A A Caputi 2
1 Department of Integrative and Computational Neurosciences, Instituto de Investigaciones Biológicas Clemente Estable, Avenue Italia 3318, Montevideo, Uruguay; Department of Histology and Embriology, Facultad de Medicina, Universidad de la República, Gral. Flores 2515, Montevideo, Uruguay. 2 Department of Integrative and Computational Neurosciences, Instituto de Investigaciones Biológicas Clemente Estable, Avenue Italia 3318, Montevideo, Uruguay
DOI: 10.1016/j.neuroscience.2013.11.021
PMID: 24269939
Pubmed: https://pubmed.ncbi.nlm.nih.gov/24269939
Texto completo: https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(13)00961-5
Abstract:
The intrinsic properties of spherical neurons play a fundamental role in the sensory processing of self-generated signals along a fast electrosensory pathway in electric fish. Previous results indicate that the spherical neuron's intrinsic properties depend mainly on the presence of two resonant currents that tend to clamp the voltage near the resting potential. Here we show that these are: a low-threshold potassium current blocked by 4-aminopyridine and a mixed cationic current blocked by cesium chloride. We also show that the low-threshold potassium current also causes the long refractory period, explaining the necessary properties that implement the dynamic filtering of the self-generated signals previously described. Comparative data from other fish and from the auditory system indicate that other single spiking onset neurons might differ in the channel repertoire observed in the spherical neurons of Gymnotus omarorum.
From the intrinsic properties to the functional role of a neuron phenotype: an example from electric fish during signal trade-off
J Exp Bio 2013 216(Pt 13):2380-92
Javier Nogueira 1 2, Angel A Caputi 2
1 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Avenida General Flores, 2125 Montevideo, Uruguay 2 Departamento de Neurociencias Integrativas y Computacionales, Instituto de Investigaciones Biológicas Clemente Estable, Avenida Italia, 3318 Montevideo, Uruguay
DOI: 10.1242/jeb.082651
PMID: 23761463
Pubmed: https://pubmed.ncbi.nlm.nih.gov/23761463
Texto completo: https://journals.biologists.com/jeb/article-lookup/doi/10.1242/jeb.082651
Abstract:
This review deals with the question: what is the relationship between the properties of a neuron and the role that the neuron plays within a given neural circuit? Answering this kind of question requires collecting evidence from multiple neuron phenotypes and comparing the role of each type in circuits that perform well-defined computational tasks. The focus here is on the spherical neurons in the electrosensory lobe of the electric fish Gymnotus omarorum. They belong to the one-spike-onset phenotype expressed at the early stages of signal processing in various sensory modalities and diverse taxa. First, we refer to the one-spike neuron intrinsic properties, their foundation on a low-threshold K(+) conductance, and the potential roles of this phenotype in different circuits within a comparative framework. Second, we present a brief description of the active electric sense of weakly electric fish and the particularities of spherical one-spike-onset neurons in the electrosensory lobe of G. omarorum. Third, we introduce one of the specific tasks in which these neurons are involved: the trade-off between self- and allo-generated signals. Fourth, we discuss recent evidence indicating a still-undescribed role for the one-spike phenotype. This role deals with the blockage of the pathway after being activated by the self-generated electric organ discharge and how this blockage favors self-generated electrosensory information in the context of allo-generated interference. Based on comparative analysis we conclude that one-spike-onset neurons may play several functional roles in animal sensory behavior. There are specific adaptations of the neuron's 'response function' to the circuit and task. Conversely, the way in which a task is accomplished depends on the intrinsic properties of the neurons involved. In short, the role of a neuron within a circuit depends on the neuron and its functional context.
Overexpression of the nuclear factor kappaB inhibitor A20 is neurotoxic after an excitotoxic injury to the immature rat brain
Neurol Res 2013 35(3):308-19
Hugo Peluffo 1 2, Pau Gonzalez 3, Laia Acarin 4, Anna Arís 5, Rudy Beyaert 6 7, Antonio Villaverde 5 8, Berta Gonzalez 4
1 Laboratorio de Neurodegeneración, Institut Pasteur de Montevideo, Uruguay 2 Laboratorio de Neurobiología Celular y Molecular, Depto. Histología y Embriología, Facultad de Medicina, UDELAR, Uruguay, 3 Laboratorio de Neurología Molecular, Hospital Nacional de Parapléjicos de Toledo, Spain, 4 Unitat d’Histologia, Torre M5, Facultat de Medicina, Departament de Biologia Cellular, Fisiologia i Immunologia, and Institut de Neurociéncies, Universitat Autònoma de Barcelona, Spain, 5 Institut de Biotecnologia i de Biomedicina and Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Spain, 6 Department of Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Belgium, 7 Department of Molecular Biology, Ghent University, Belgium, 8CIBER de Bioingenierı ´a, Biomateriales y Nanomedicina (CIBER-BBN), Bellaterra, Barcelona, Spain
DOI: 10.1179/1743132812Y.0000000139
PMID: 23336395
Pubmed: https://pubmed.ncbi.nlm.nih.gov/23336395
Texto completo: https://www.tandfonline.com/doi/full/10.1179/1743132812Y.0000000139
Abstract:
Background: The zinc finger protein A20 is an ubiquitinating/deubiquitinating enzyme essential for the termination of inflammatory reactions through the inhibition of nuclear factor kappaB (NF-kappaB) signaling. Moreover, it also shows anti-apoptotic activities in some cell types and proapoptotic/pronecrotic effects in others. Although it is known that the regulation of inflammatory and cell death processes are critical in proper brain functioning and that A20 mRNA is expressed in the CNS, its role in the brain under physiological and pathological conditions is still unknown.
Methods: In the present study, we have evaluated the effects of A20 overexpression in mixed cortical cultures in basal conditions: the in vivo pattern of endogenous A20 expression in the control and N-methyl-d-aspartate (NMDA) excitotoxically damaged postnatal day 9 immature rat brain, and the post-injury effects of A20 overexpression in the same lesion model.
Results: Our results show that overexpression of A20 in mixed cortical cultures induced significant neuronal death by decreasing neuronal cell counts by 45 ± 9%. in vivo analysis of endogenous A20 expression showed widespread expression in gray matter, mainly in neuronal cells. However, after NMDA-induced excitotoxicity, neuronal A20 was downregulated in the neurodegenerating cortex and striatum at 10-24 hours post-lesion, and it was re-expressed at longer survival times in reactive astrocytes located mainly in the lesion border. When A20 was overexpressed in vivo 2 hours after the excitotoxic damage, the lesion volume at 3 days post-lesion showed a significant increase (20.8 ± 7.0%). No A20-induced changes were observed in the astroglial response to injury.
Conclusions: A20 is found in neuronal cells in normal conditions and is also expressed in astrocytes after brain damage, and its overexpression is neurotoxic for cortical neurons in basal mixed neuron-glia culture conditions and exacerbates postnatal brain excitotoxic damage.
Convergence of multiple mechanisms of steroid hormone action
Horm Metab Res 2012 44(8):569-76
S K Mani 1 *, P G Mermelstein 2 *, M J Tetel 3 *, G Anesetti 4 *
1 Department of Molecular & Cellular Biology and Neuroscience, Baylor College of Medicine, Houston, TX, USA 2 Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA 3 Neuroscience Program, Wellesley College, Wellesley, MA, USA 4 Departamento de Hostologia y Embriologia, Facultad de Medicine, Universidad de la Republica, Montevideo, Uruguay *All the authors contributed equally to this work.
DOI: 10.1055/s-0032-1306343
PMID: 22454239
Pubmed: https://pubmed.ncbi.nlm.nih.gov/22454239
Texto completo: https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0032-1306343
Abstract:
Steroid hormones modulate a wide array of physiological processes including development, metabolism, and reproduction in various species. It is generally believed that these biological effects are predominantly mediated by their binding to specific intracellular receptors resulting in conformational change, dimerization, and recruitment of coregulators for transcription-dependent genomic actions (classical mechanism). In addition, to their cognate ligands, intracellular steroid receptors can also be activated in a "ligand-independent" manner by other factors including neurotransmitters. Recent studies indicate that rapid, nonclassical steroid effects involve extranuclear steroid receptors located at the membrane, which interact with cytoplasmic kinase signaling molecules and G-proteins. The current review deals with various mechanisms that function together in an integrated manner to promote hormone-dependent actions on the central and sympathetic nervous systems.
Overexpression of the immunoreceptor CD300f has a neuroprotective role in a model of acute brain injury
Brain Pathol 2012 22(3):318-28
Hugo Peluffo 1 2, Daniela Alí‐Ruiz 1 2, Aroa Ejarque‐Ortíz 3 7, Victor Heras‐Alvarez 3 7, Emma Comas‐Casellas 3 7, Agueda Martínez‐Barriocanal 3 7, Andres Kamaid 1, Damiana Alvarez‐Errico 8, Maria Luciana Negro 1 2, Natalia Lago 2, Simó Schwartz Jr 4 7, Antonio Villaverde 5 6 7, Joan Sayós 3 7
1 Department of Histology and Embryology, Faculty of Medicine, UDELAR, Montevideo, Uruguay. 2 Neurodegeneration Laboratory, Institut Pasteur de Montevideo, Montevideo, Uruguay. 3 Immunobiology Group, CIBBIM‐Nanomedicine Program, Hospital Universitari Vall d'Hebrón, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain. 4 Drug Delivery and Targeting Group, CIBBIM‐Nanomedicine Program, Hospital Universitari Vall d'Hebrón, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain. 5 Institute for Biotechnology and Biomedicine, Barcelona, Spain. 6 Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Barcelona, Spain. 7 Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER‐BBN), Instituto de Salud Carlos III. 8 Unitat de Bioquímica, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
DOI: 10.1111/j.1750-3639.2011.00537.x
PMID: 21951326
Pubmed: https://pubmed.ncbi.nlm.nih.gov/21951326
Texto completo: https://doi.org/10.1111/j.1750-3639.2011.00537.x
Abstract:
It is well known that cell surface immune receptors play a critical role in regulating immune and inflammatory processes in the central nervous system (CNS). We have analyzed the function of cluster of differentiation (CD)300f immunoreceptor in a model of excitotoxic rat brain damage. First, to explore the presence of endogenous ligand(s) for this receptor we used a human CD300f-Ig soluble protein and confocal microscopy, showing specific staining mainly in CNS white matter and on the surface of oligodendrocytes and certain astrocytes. Next, we demonstrated in a model of in vivo rat brain excitotoxic damage that the overexpression of human CD300f induced a significant reduction in the lesion volume. To validate these results, we cloned the rat ortholog of CD300f protein (rCD300f). The overexpression of rCD300f receptor had a comparable neuroprotective effect after the acute brain injury and a similar CNS staining pattern when stained with the rCD300f-Ig soluble protein. Interestingly, when we analyzed the expression pattern of rCD300f in brain cells by quantitative polymerase chain reaction and immunohistochemistry, we detected the expression of CD300f as expected in microglial cells, but also in oligodendrocytes and neurons. These data suggest that the neuroprotective role of CD300f would be the result of a complex network of cell interactions.
Involvement of the oestrogenic receptors in superior mesenteric ganglion on the ovarian steroidogenesis in rat
Reproduction 2012 143(2):183-93
Adriana Vega Orozco, Cristina Daneri, Gabriel Anesetti 1, Ricardo Cabrera 2 3, Zulema Sosa, Ana M Rastrilla
Laboratorio de Biología de la Reproducción (LABIR), Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis, Argentina, 1 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, General Flores 2125, CP 11800 Montevideo, Uruguay, 2 Instituto de Ciencias Biomédicas, Facultad de Ciencias Médicas, Universidad de Mendoza, Mendoza, Argentina and 3 Instituto de Medicina y Biología Experimental de Cuyo (IMBECU)-Consejo National de Investigaciones Científicas y Technológicas (CONICET), Mendoza, Argentina
DOI: 10.1530/REP-11-0056
PMID: 22080140
Pubmed: https://pubmed.ncbi.nlm.nih.gov/22080140
Texto completo: https://rep.bioscientifica.com/doi/10.1530/REP-11-0056
Abstract:
Oestradiol (E(2)) is a key hormone in the regulation of reproductive processes. The aims of this work were a) to examine the distributions of oestrogen receptor α (ERα) and ERβ in the neurons of the superior mesenteric ganglion (SMG) in the oestrus stage by immunohistochemistry, b) to demonstrate whether E(2) in the SMG modifies progesterone (P(4)), androstenedione (A(2)) and nitrite release in the ovarian compartment on oestrus day and c) to demonstrate whether E(2) in the ganglion modifies the activity and gene expression in the ovary of the steroidogenic enzymes 3β-hydroxysteroid dehydrogenase (3β-HSD) and 20α-hydroxysteroid dehydrogenase (20α-HSD). The ex vivo SMG-ovarian nervous plexus-ovary system was used. E(2), tamoxifen (Txf) and E(2) plus Txf were added in the ganglion to measure ovarian P(4) release, while E(2) alone was added to measure ovarian A(2) and nitrites release. Immunohistochemistry revealed cytoplasmic ERα immunoreactivity only in the neural somas in the SMG. E(2) increased ovarian P(4) and A(2) release at 15, 30 and 60 min but decreased nitrites. The activity and gene expression of 3β-HSD increased, while the activity and gene expression of 20α-HSD did not show changes with respect to the control. Txf in the ganglion diminished P(4) release only at 60 min. E(2) plus Txf in the ganglion reverted the effect of E(2) alone and the inhibitory effect of Txf. The results of this study demonstrate that ERα activation in the SMG has an impact on ovarian steroidogenesis in rats, thus providing evidence for the critical role of peripheral system neurons in the control of ovarian functions under normal and pathological conditions.
DNA sperm damage correlates with nuclear ultrastructural sperm defects in teratozoospermic men
Andrologia 2012 44(1):59-65
F Skowronek 1 2, G Casanova 2, J Alciaturi 1, A Capurro 3, L Cantu 4, J M Montes 4, R Sapiro 1
1 Laboratory of Molecular Biology of Reproduction, Department of Histology & Embryology, School of Medicine, Montevideo, Uruguay; 2 Department of Cellular and Molecular Biology and Electron Microscopy Unit, School of Science, Montevideo, Uruguay; 3 Unit of Human Reproduction, Pereira-Rossell Hospital Center, Montevideo, Uruguay; 4 Fertilab Canelones, Montevideo, Uruguay
DOI: 10.1111/j.1439-0272.2010.01106.x
PMID: 21592172
Pubmed: https://pubmed.ncbi.nlm.nih.gov/21592172
Texto completo: https://doi.org/10.1111/j.1439-0272.2010.01106.x
Abstract:
Sperm morphology has consistently been the best indicator of male fertility. Transmission electron microscopy currently provides the most information on the subcellular details of sperm structure. Recently, assessment of sperm DNA damage has been employed to assess fertility potential. The purpose of this work was to link sperm DNA damage, evaluated by an intercalated fluorescent dye, with the structural characteristics of sperm. Conventional semen analysis was performed on samples from men undergoing fertility evaluation. Thirty men were evaluated and assigned to three subgroups based on strict criteria for sperm morphology: normal morphology (>14% normal forms), intermediate morphology (5-14% normal forms), and poor morphology (<5% normal forms). By quantifying acridine orange-positive cells and ultrastructural sperm defects, we found that the poor morphology pattern group showed a positive association between sperm carrying damaged DNA and the percentage of sperm nucleus with vacuoles (P = 0.01). No statistically significant correlations were established in other ultrastructural characteristics of sperm, including immature chromatin, lytic changes, or abnormal sperm tails. These results suggest that zones without chromatin in the sperm nucleus reflect underlying chromosomal or DNA defects in severe teratozoospermic men. This association should be considered in the evaluation of male fertility.
Rapid multiplex high resolution melting method to analyze inflammatory related SNPs in preterm birth
BMC Res Notes 2012 5:69
Silvana Pereyra 1 2, Tatiana Velazquez 1, Bernardo Bertoni 1, Rossana Sapiro 2
1 Departament of Genetics, School of Medicine, University of the Republic, Gral. Flores 2125, Montevideo, Uruguay 2 Departament of Histology and Embryology, School of Medicine, University of the Republic, Gral. Flores 2125, Montevideo, Uruguay
DOI: 10.1186/1756-0500-5-69
PMID: 22280494
Pubmed: https://pubmed.ncbi.nlm.nih.gov/22280494
Texto completo: https://bmcresnotes.biomedcentral.com/articles/10.1186/1756-0500-5-69
Abstract:
Background: Complex traits like cancer, diabetes, obesity or schizophrenia arise from an intricate interaction between genetic and environmental factors. Complex disorders often cluster in families without a clear-cut pattern of inheritance. Genomic wide association studies focus on the detection of tens or hundreds individual markers contributing to complex diseases. In order to test if a subset of single nucleotide polymorphisms (SNPs) from candidate genes are associated to a condition of interest in a particular individual or group of people, new techniques are needed. High-resolution melting (HRM) analysis is a new method in which polymerase chain reaction (PCR) and mutations scanning are carried out simultaneously in a closed tube, making the procedure fast, inexpensive and easy. Preterm birth (PTB) is considered a complex disease, where genetic and environmental factors interact to carry out the delivery of a newborn before 37 weeks of gestation. It is accepted that inflammation plays an important role in pregnancy and PTB.
Methods: Here, we used real time-PCR followed by HRM analysis to simultaneously identify several gene variations involved in inflammatory pathways on preterm labor. SNPs from TLR4, IL6, IL1 beta and IL12RB genes were analyzed in a case-control study. The results were confirmed either by sequencing or by PCR followed by restriction fragment length polymorphism.
Results: We were able to simultaneously recognize the variations of four genes with similar accuracy than other methods. In order to obtain non-overlapping melting temperatures, the key step in this strategy was primer design. Genotypic frequencies found for each SNP are in concordance with those previously described in similar populations. None of the studied SNPs were associated with PTB.
Conclusions: Several gene variations related to the same inflammatory pathway were screened through a new flexible, fast and non expensive method with the purpose of analyzing their association to PTB. It can easily be used for simultaneously analyze any set of SNPs, either as the first choice for new association studies or as a complement to large-scale genotyping analysis. Given that inflammatory pathway is in the base of several diseases, it is potentially useful to analyze a broad range of disorders.
Modulation of astrocytic mitochondrial function by dichloroacetate improves survival and motor performance in inherited amyotrophic lateral sclerosis
PLoS One 2012 7(4):e34776
Ernesto Miquel 1 #, Adriana Cassina 2 3 #, Laura Martínez-Palma 1, Carmen Bolatto 1, Emiliano Trías 4, Mandi Gandelman 1, Rafael Radi 2 3, Luis Barbeito 5 3, Patricia Cassina 1 3
1 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay 2 Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay 3 CEINBIO, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay 4 Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay 5 Institut Pasteur de Montevideo, Montevideo, Uruguay 6 Federal University of Rio de Janeiro, Brazil
DOI: 10.1371/journal.pone.0034776
PMID: 22509356
Pubmed: https://pubmed.ncbi.nlm.nih.gov/22509356
Texto completo: https://dx.plos.org/10.1371/journal.pone.0034776
Abstract:
Mitochondrial dysfunction is one of the pathogenic mechanisms that lead to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). Astrocytes expressing the ALS-linked SOD1(G93A) mutation display a decreased mitochondrial respiratory capacity associated to phenotypic changes that cause them to induce motor neuron death. Astrocyte-mediated toxicity can be prevented by mitochondria-targeted antioxidants, indicating a critical role of mitochondria in the neurotoxic phenotype. However, it is presently unknown whether drugs currently used to stimulate mitochondrial metabolism can also modulate ALS progression. Here, we tested the disease-modifying effect of dichloroacetate (DCA), an orphan drug that improves the functional status of mitochondria through the stimulation of the pyruvate dehydrogenase complex activity (PDH). Applied to astrocyte cultures isolated from rats expressing the SOD1(G93A) mutation, DCA reduced phosphorylation of PDH and improved mitochondrial coupling as expressed by the respiratory control ratio (RCR). Notably, DCA completely prevented the toxicity of SOD1(G93A) astrocytes to motor neurons in coculture conditions. Chronic administration of DCA (500 mg/L) in the drinking water of mice expressing the SOD1(G93A) mutation increased survival by 2 weeks compared to untreated mice. Systemic DCA also normalized the reduced RCR value measured in lumbar spinal cord tissue of diseased SOD1(G93A) mice. A remarkable effect of DCA was the improvement of grip strength performance at the end stage of the disease, which correlated with a recovery of the neuromuscular junction area in extensor digitorum longus muscles. Systemic DCA also decreased astrocyte reactivity and prevented motor neuron loss in SOD1(G93A) mice. Taken together, our results indicate that improvement of the mitochondrial redox status by DCA leads to a disease-modifying effect, further supporting the therapeutic potential of mitochondria-targeted drugs in ALS.