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Óscar G. Vidaurre

Instituto de Investigaciones Biomédicas Sols-Morreale

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Margarita Díaz‐Guerra

Universidad Autónoma de Madrid

Patrizia Casaccia

The Graduate Center, CUNY

Jeffery D. Haines

Regeneron (United States)

Angeles Rodrı́guez-Peña

University Hospital Schleswig-Holstein

Kadidia P. Adula

University of California, Los Angeles

Gonzalo S. Tejeda

University of Glasgow

Sergio Gascón

Instituto Cajal

Gema M. Esteban-Ortega

Universidad Autónoma de Madrid

Mónica Sobrado

Hospital Universitario de La Princesa

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Ángela L. Riffo‐Campos

Universitat de València

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Icahn School of Medicine at Mount Sinai

Universidad Autónoma de Madrid

Consejo Superior de Investigaciones Científicas

Instituto de Investigaciones Biomédicas Sols-Morreale

Allen Institute for Brain Science

Johns Hopkins University

Universitat de València

Johns Hopkins Medicine

Instituto de Salud Carlos III

Johns Hopkins Hospital

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Cerebrospinal fluid ceramides from patients with multiple sclerosis impair neuronal bioenergetics

Brain (2014)

Óscar G. Vidaurre Jeffery D. Haines Ilana Katz Sand Kadidia P. Adula Jimmy Huynh

Axonal damage is a prominent cause of disability and yet its pathogenesis is incompletely understood. Using a xenogeneic system, here we define the bioenergetic changes induced in rat neurons by exposure to cerebrospinal fluid samples from patients with multiple sclerosis compared to control subjects. A first discovery cohort of cerebrospinal fluid from 13 patients with multiple sclerosis and 10 control subjects showed that acute exposure to cerebrospinal fluid from patients with multiple sclerosis induced oxidative stress and decreased expression of neuroprotective genes, while increasing expression of genes involved in lipid signalling and in the response to oxidative stress. Protracted exposure of neurons to stress led to neurotoxicity and bioenergetics failure after cerebrospinal fluid exposure and positively correlated with the levels of neurofilament light chain. These findings were validated using a second independent cohort of cerebrospinal fluid samples (eight patients with multiple sclerosis and eight control subjects), collected at a different centre. The toxic effect of cerebrospinal fluid on neurons was not attributable to differences in IgG content, glucose, lactate or glutamate levels or differences in cytokine levels. A lipidomic profiling approach led to the identification of increased levels of ceramide C16:0 and C24:0 in the cerebrospinal fluid from patients with multiple sclerosis. Exposure of cultured neurons to micelles composed of these ceramide species was sufficient to recapitulate the bioenergetic dysfunction and oxidative damage induced by exposure to cerebrospinal fluid from patients with multiple sclerosis. Therefore, our data suggest that C16:0 and C24:0 ceramides are enriched in the cerebrospinal fluid of patients with multiple sclerosis and are sufficient to induce neuronal mitochondrial dysfunction and axonal damage.

Neurotoxicity

10.1093/brain/awu139

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Citations (138)

Subcellular Distribution of HDAC1 in Neurotoxic Conditions Is Dependent on Serine Phosphorylation

Journal of Neuroscience (2017)

Yunjiao Zhu Óscar G. Vidaurre Kadidia P. Adula Nebojsa Kezunovic Maureen Wentling

Calcium-dependent nuclear export of histone deacetylase 1 (HDAC1) was shown previously to precede axonal damage in culture, but the in vivo relevance of these findings and the potential posttranslational modifications of HDAC1 remained elusive. Using acute hippocampal slices from mice of either sex with genetic conditional ablation of Hdac1 in CA1 hippocampal neurons (i.e., Camk2a-cre;Hdac1^fl/fl), we show significantly diminished axonal damage in response to neurotoxic stimuli. The protective effect of Hdac1 ablation was detected also in CA3 neurons in Grik4-cre;Hdac1^fl/f mice, which were more resistant to the excitotoxic damage induced by intraventricular injection of kainic acid. The amino acid residues modulating HDAC1 subcellular localization were identified by site-directed mutagenesis, which identified serine residues 421 and 423 as critical for its nuclear localization. The physiological phosphorylation of HDAC1 was decreased by neurotoxic stimuli, which stimulated the phosphatase enzymatic activity of calcineurin. Treatment of neurons with the calcineurin inhibitors FK506 or cyclosporin A resulted in nuclear accumulation of phospho-HDAC1 and was neuroprotective. Together, our data identify HDAC1 and the phosphorylation of specific serine residues in the molecule as potential targets for neuroprotection. SIGNIFICANCE STATEMENT The importance of histone deacetylation in normal brain functions and pathological conditions is unquestionable, yet the molecular mechanisms responsible for the neurotoxic potential of histone deacetylase 1 (HDAC1) and its subcellular localization are not fully understood. Here, we use transgenic lines to define the in vivo relevance of HDAC1 and identify calcineurin-dependent serine dephosphorylation as the signal modulating the neurotoxic role of HDAC1 in response to neurotoxic stimuli.

HDAC1

10.1523/jneurosci.3000-16.2017

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Kidins220/ARMS downregulation by excitotoxic activation of NMDARs reveals its involvement in neuronal survival and death pathways

Journal of Cell Science (2009)

Celia López‐Menéndez Sergio Gascón Mónica Sobrado Óscar G. Vidaurre Alonso M. Higuero

Functional and protein interactions between the N-methyl-D-aspartate type of glutamate receptor (NMDAR) and neurotrophin or ephrin receptors play essential roles in neuronal survival and differentiation. A shared downstream effector for neurotrophin- and ephrin-receptor signaling is kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS). Because this molecule is obligatory for neurotrophin-induced differentiation, we investigated whether Kidins220/ARMS and NMDAR functions were related. Here, we identify an association between these proteins and discover that excitotoxicity, a specific form of neuronal death induced by NMDAR overstimulation, dramatically decreases Kidins220/ARMS levels in cortical neurons and in a model of cerebral ischemia. Kidins220/ARMS downregulation is triggered by overactivation of NMDARs containing NR2B subunits and subsequent Ca2+ influx, and involves a dual mechanism: rapid cleavage by the Ca2+-dependent protease calpain and calpain-independent silencing of Kidins220/Arms gene transcription. Additionally, Kidins220/ARMS knockdown decreases ERK activation and basal neuronal viability, and enhances neuronal death under excitotoxic conditions. Our results demonstrate Kidins220/ARMS participation in neuronal life and death pathways, and constitute the first report of its regulation under pathological conditions.

Excitotoxicity

10.1242/jcs.056473

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Citations (61)

Multiple sclerosis patient-derived CSF induces transcriptional changes in proliferating oligodendrocyte progenitors

Multiple Sclerosis Journal (2015)

Jeffery D. Haines Óscar G. Vidaurre Fan Zhang Ángela L. Riffo‐Campos Josefa Castillo

Background: Cerebrospinal fluid (CSF) is in contact with brain parenchyma and ventricles, and its composition might influence the cellular physiology of oligodendrocyte progenitor cells (OPCs) thereby contributing to multiple sclerosis (MS) disease pathogenesis. Objective: To identify the transcriptional changes that distinguish the transcriptional response induced in proliferating rat OPCs upon exposure to CSF from primary progressive multiple sclerosis (PPMS) or relapsing remitting multiple sclerosis (RRMS) patients and other neurological controls. Methods: We performed gene microarray analysis of OPCs exposed to CSF from neurological controls, or definitive RRMS or PPMS disease course. Results were confirmed by quantitative reverse transcriptase polymerase chain reaction, immunocytochemistry and western blot of cultured cells, and validated in human brain specimens. Results: We identified common and unique oligodendrocyte genes for each treatment group. Exposure to CSF from PPMS uniquely induced branching of cultured progenitors and related transcriptional changes, including upregulation ( P<0.05) of the adhesion molecule GALECTIN-3/ Lgals3, which was also detected at the protein level in brain specimens from PPMS patients. This pattern of gene expression was distinct from the transcriptional programme of oligodendrocyte differentiation during development. Conclusions: Despite evidence of morphological differentiation induced by exposure to CSF of PPMS patients, the overall transcriptional response elicited in cultured OPCs was consistent with the activation of an aberrant transcriptional programme.

Parenchyma

10.1177/1352458515573094

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Citations (18)

Regulación de proteínas en la disyuntiva supervivencia/muerte neuronal en excitotoxicidad e isquemia cerebral: TrkB y PSD-95

Óscar G. Vidaurre

Regulacion de proteinas en la disyuntiva supervivencia/muerte neuronal en excitoxicidad e isquemia cerebral: Trkb y psd-95

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Imbalance of neurotrophin receptor isoforms TrkB-FL/TrkB-T1 induces neuronal death in excitotoxicity

Cell Death and Disease (2012)

Óscar G. Vidaurre Sergio Gascón Rubén Deogracias Mónica Sobrado Eloy Cuadrado

A better understanding of the mechanisms underlying neuronal death in cerebral ischemia is required for the development of stroke therapies. Here we analyze the contribution of the tropomyosin-related kinase B (TrkB) neurotrophin receptor to excitotoxicity, a primary pathological mechanism in ischemia, which is induced by overstimulation of glutamate receptors of the N-methyl-D-aspartate type. We demonstrate a significant modification of TrkB expression that is strongly associated with neurodegeneration in models of ischemia and in vitro excitotoxicity. Two mechanisms cooperate for TrkB dysregulation: (1) calpain-processing of full-length TrkB (TrkB-FL), high-affinity receptor for brain-derived neurotrophic factor, which produces a truncated protein lacking the tyrosine-kinase domain and strikingly similar to the inactive TrkB-T1 isoform and (2) reverse regulation of the mRNA of these isoforms. Collectively, excitotoxicity results in a decrease of TrkB-FL, the production of truncated TrkB-FL and the upregulation of TrkB-T1. A similar neuro-specific increase of the TrkB-T1 isoform is also observed in stroke patients. A lentivirus designed for both neuro-specific TrkB-T1 interference and increased TrkB-FL expression allows recovery of the TrkB-FL/TrkB-T1 balance and protects neurons from excitotoxic death. These data implicate a combination of TrkB-FL downregulation and TrkB-T1 upregulation as significant causes of neuronal death in excitotoxicity, and reveal novel targets for the design of stroke therapies.

Excitotoxicity

Trk receptor

10.1038/cddis.2011.143

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Citations (91)

A novel cell-penetrating peptide targeting calpain-cleavage of PSD-95 induced by excitotoxicity improves neurological outcome after stroke

Theranostics (2021)

Sara Ayuso‐Dolado Gema M. Esteban-Ortega Óscar G. Vidaurre Margarita Díaz‐Guerra

Postsynaptic density protein-95 (PSD-95) is a multidomain protein critical to the assembly of signaling complexes at excitatory synapses, required for neuronal survival and function.However, calpainprocessing challenges PSD-95 function after overactivation of excitatory glutamate receptors (excitotoxicity) in stroke, a leading cause of death, disability and dementia in need of efficient pharmacological treatments.A promising strategy is neuroprotection of the infarct penumbra, a potentially recoverable area, by promotion of survival signaling.Interference of PSD-95 processing induced by excitotoxicity might thus be a therapeutic target for stroke and other excitotoxicityassociated pathologies.Methods: The nature and stability of PSD-95 calpain-fragments was analyzed using in vitro assays or excitotoxic conditions induced in rat primary neuronal cultures or a mouse model of stroke.We then sequenced PSD-95 cleavage-sites and rationally designed three cell-penetrating peptides (CPPs) containing these sequences.The peptides effects on PSD-95 stability and neuronal viability were investigated in the cultured neurons, subjected to acute or chronic excitotoxicity.We also analyzed the effect of one of these peptides in the mouse model of stroke by measuring infarct size and evaluating motor coordination and balance.Results: Calpain cleaves three interdomain linker regions in PSD-95 and produces stable fragments corresponding to previously described PSD-95 supramodules (PDZ1-2 and P-S-G) as well as a truncated form SH3-GK. Peptide TP95414, containing the cleavage site in the PDZ3-SH3 linker, is able to interfere PSD-95 downregulation and reduces neuronal death by excitotoxicity.Additionally, TP95414 is delivered to mice cortex and, in a severe model of permanent ischemia, significantly improves the neurological outcome after brain damage.Conclusions: Interference of excitotoxicity-induced PSD-95-processing with specific CPPs constitutes a novel and promising therapeutic approach for stroke treatment.

Excitotoxicity

Postsynaptic density

10.7150/thno.60701

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Citations (19)

CSF from MS Patients Induces Mitochondrial Dysfunction in Unmyelinated Neuronal Cultures (P05.179)

Neurology (2013)

Ilana Katz Sand Óscar G. Vidaurre Jeffery D. Haines Kadidia P. Adula Corey McGraw

OBJECTIVE: To determine the effect of CSF of MS patients on neuronal mitochondrial function.

10.1212/wnl.80.7_supplement.p05.179

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An integrated approach to design novel therapeutic interventions for demyelinating disorders

European Journal of Neuroscience (2012)

Óscar G. Vidaurre Jia Liu Jeffery D. Haines Juan Sandoval Richard S. Nowakowski

Abstract Therapeutic strategies are often based on two general principles: interference with the pathogenic process and repair of the damaged tissues. Recent studies, however, have suggested that several pathological conditions may result from the interplay between genetic susceptibility traits and environmental influences that, by modulating the epigenome, also affect disease onset and progression. Based on lessons from neural development, it is conceivable that new lines of preventive and possibly therapeutic intervention might be developed to modulate disease onset or decrease the severity of the symptoms. This review will discuss these concepts within the context of multiple sclerosis, the most common demyelinating disease of the central nervous system, and the leading cause of progressive neurological disability in young adults.

Demyelinating disease

Demyelinating Disorder

Epigenome

Genetic predisposition

10.1111/j.1460-9568.2012.08118.x

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Citations (23)

Bioenergetic Failure in Rat Oligodendrocyte Progenitor Cells Treated with Cerebrospinal Fluid Derived from Multiple Sclerosis Patients

Frontiers in Cellular Neuroscience (2017)

Deepali Mathur Ángela L. Riffo‐Campos Josefa Castillo Jeffery D. Haines Óscar G. Vidaurre

In relapsing-remitting multiple sclerosis (RRMS) subtype, the patient's brain itself is capable of repairing the damage, remyelinating the axon and recovering the neurological function. Cerebrospinal fluid (CSF) is in close proximity with brain parenchyma and contains a host of proteins and other molecules, which influence the cellular physiology, that may balance damage and repair of neurons and glial cells. The purpose of this study was to determine the pathophysiological mechanisms underpinning myelin repair in distinct clinical forms of MS and neuromyelitis optica (NMO) patients by studying the effect of diseased CSF on glucose metabolism and ATP synthesis. A cellular model with primary cultures of oligodendrocyte progenitor cells (OPCs) from rat cerebrum was employed, and cells were treated with CSF from distinct clinical forms of MS, NMO patients and neurological controls. Prior to comprehending mechanisms underlying myelin repair, we determine the best stably expressed reference genes in our experimental condition to accurately normalize our target mRNA transcripts. The GeNorm and NormFinder algorithms showed that mitochondrial ribosomal protein (Mrpl19), hypoxanthine guanine phosphoribosyl transferase (Hprt), microglobulin β2 (B2m), and transferrin receptor (Tfrc) were identified as the best reference genes in OPCs treated with MS subjects and were used for normalizing gene transcripts. The main findings on microarray gene expression profiling analysis on CSF treated OPCs cells revealed a disturbed carbohydrate metabolism and ATP synthesis in MS and NMO derived CSF treated OPCs. In addition, using STRING program, we investigate whether gene-gene interaction affected the whole network in our experimental conditions. Our findings revealed downregulated expression of genes involved in carbohydrate metabolism, and that glucose metabolism impairment and reduced ATP availability for cellular damage repair clearly differentiate more benign forms from the most aggressive forms and worst prognosis in MS patients.

Remyelination

10.3389/fncel.2017.00209

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Citations (12)