Carmen R. Sunico

Sanford Burnham Prebys Medical Discovery Institute

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Bernardo Moreno‐López

Universidad de Cádiz

Stuart A. Lipton

University of California, San Diego

Tomohiro Nakamura

Scripps Research Institute

David González‐Forero

Biomedical Research and Innovation Institute of Cadiz

Federico Portillo

Universidad de Cádiz

Nobuki Nakanishi

Scintillon Institute

Eliezer Masliah

University of California, San Diego

Mohd Waseem Akhtar

Bahauddin Zakariya University

James Parker

Scintillon Institute

Bing Shan

Shanghai Institute of Organic Chemistry

Cooperative Institutions

Sanford Burnham Prebys Medical Discovery Institute

Discovery Institute

Scintillon Institute

University of California, San Diego

Scripps Research Institute

University of Bristol

Iwate University

Universidad de Cádiz

National Institutes of Health

Chinese Academy of Sciences

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Nitric Oxide-Directed Synaptic Remodeling in the Adult Mammal CNS

Journal of Neuroscience (2005)

Carmen R. Sunico Federico Portillo David González‐Forero Bernardo Moreno‐López

In adult mammals, learning, memory, and restoration of sensorimotor lost functions imply synaptic reorganization that requires diffusible messengers-mediated communication between presynaptic and postsynaptic structures. A candidate molecule to accomplish this function is the gaseous intercellular messenger nitric oxide (NO), which is involved in synaptogenesis and projection refinement during development; however, the role of NO in synaptic reorganization processes in adulthood remains to be established. In this work, we tested the hypothesis that this free radical is a mediator in the adult mammal CNS synaptic remodeling processes using a model of hypoglossal axonal injury recently developed by us. Axonal injury-induced disconnection of motoneurons from myocytes produces withdrawal of synaptic inputs to motoneurons and concomitant upregulation of the neuronal isoform of NO synthase (NOS-I). After recovery of the neuromuscular function, synaptic coverage is reestablished and NOS-I is downregulated. We also report, by using functional and morphological approaches, that chronic inhibition of the NO/cGMP pathway prevents synaptic withdrawal evoked by axon injury, despite the persistent muscle disconnection. After successful withdrawal of synaptic boutons, inhibition of NO synthesis, but not of cGMP, accelerated the recovery of synaptic coverage, although neuromuscular disconnection was maintained. Furthermore, protein S -nitrosylation was upregulated after nerve injury, and this effect was reversed by NOS-I inhibition. Our results suggest that during synaptic remodeling in the adult CNS, NO acts as a signal for synaptic detachment and inhibits synapse formation by cGMP-dependent and probably S -nitrosylation-mediated mechanisms, respectively. We also suggest a feasible role of NO in neurological disorders coursing with NOS-I upregulation.

Synaptogenesis

Soluble guanylyl cyclase

Retrograde signaling

10.1523/jneurosci.4600-04.2005

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Citations (90)

S-Nitrosylation of parkin as a novel regulator of p53-mediated neuronal cell death in sporadic Parkinson’s disease

Molecular Neurodegeneration (2013)

Carmen R. Sunico Tomohiro Nakamura Edward Rockenstein Michael Mante Anthony Adame

Abstract Background Mutations in the gene encoding parkin, a neuroprotective protein with dual functions as an E3 ubiquitin ligase and transcriptional repressor of p53, are linked to familial forms of Parkinson’s disease (PD). We hypothesized that oxidative posttranslational modification of parkin by environmental toxins may contribute to sporadic PD. Results We first demonstrated that S-nitrosylation of parkin decreased its activity as a repressor of p53 gene expression, leading to upregulation of p53. Chromatin immunoprecipitation as well as gel-shift assays showed that parkin bound to the p53 promoter, and this binding was inhibited by S-nitrosylation of parkin. Additionally, nitrosative stress induced apoptosis in cells expressing parkin, and this death was, at least in part, dependent upon p53. In primary mesencephalic cultures, pesticide-induced apoptosis was prevented by inhibition of nitric oxide synthase (NOS). In a mouse model of pesticide-induced PD, both S-nitrosylated (SNO-)parkin and p53 protein levels were increased, while administration of a NOS inhibitor mitigated neuronal death in these mice. Moreover, the levels of SNO-parkin and p53 were simultaneously elevated in postmortem human PD brain compared to controls. Conclusions Taken together, our data indicate that S-nitrosylation of parkin, leading to p53-mediated neuronal cell death, contributes to the pathophysiology of sporadic PD.

S-Nitrosylation

10.1186/1750-1326-8-29

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Redox Regulation of Protein Function via Cysteine S-Nitrosylation and Its Relevance to Neurodegenerative Diseases

International Journal of Cell Biology (2012)

Mohd Waseem Akhtar Carmen R. Sunico Tomohiro Nakamura Stuart A. Lipton

Debilitating neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), can be attributed to neuronal cell damage in specific brain regions. An important hallmark of these diseases is increased oxidative and nitrosative stress that occurs via overproduction of highly reactive free radicals known as reactive oxygen species (ROS) and reactive nitrogen species (RNS). These molecules are normally removed by cellular antioxidant systems. Under physiological conditions, ROS/RNS are present at low levels, mediating several neurotrophic and neuroprotective signaling pathways. In contrast, under pathological conditions, there is a pronounced increase in ROS/RNS generation, impairing normal neurological function. Nitric oxide (NO) is one such molecule that functions as a signaling agent under physiological conditions but causes nitrosative stress under pathological conditions due to its enhanced production. As first reported by our group and colleagues, the toxic effects of NO can be in part attributed to thiol S-nitrosylation, a posttranslational modification of cysteine residues on specific proteins. Here, we review several reports appearing over the past decade showing that S-nitrosylation of an increasing number of proteins compromises important cellular functions, including mitochondrial dynamics, endoplasmic reticulum (ER) protein folding, and signal transduction, thereby promoting synaptic damage, cell death, and neurodegeneration.

S-Nitrosylation

Reactive nitrogen species

Nitrosylation

10.1155/2012/463756

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Reduction in the Motoneuron Inhibitory/Excitatory Synaptic Ratio in an Early‐Symptomatic Mouse Model of Amyotrophic Lateral Sclerosis

Brain Pathology (2010)

Carmen R. Sunico Germán Domínguez-Vías José Manuel García‐Verdugo Rosario Osta Fernando Montero

Abstract Excitotoxicity is a widely studied mechanism underlying motoneuron degeneration in amyotrophic lateral sclerosis (ALS). Synaptic alterations that produce an imbalance in the ratio of inhibitory/excitatory synapses are expected to promote or protect against motoneuron excitotoxicity. In ALS patients, motoneurons suffer a reduction in their synaptic coverage, as in the transition from the presymptomatic (2‐month‐old) to early‐symptomatic (3‐month‐old) stage of the hSOD1 G93A mouse model of familial ALS. Net synapse loss resulted from inhibitory bouton loss and excitatory synapse gain. Furthermore, in 3‐month‐old transgenic mice, remaining inhibitory but not excitatory boutons attached to motoneurons showed reduction in the active zone length and in the spatial density of synaptic vesicles in the releasable pool near the active zone. Bouton degeneration/loss seems to be mediated by bouton vacuolization and by mechanical displacement due to swelling vacuolated dendrites. In addition, chronic treatment with a nitric oxide (NO) synthase inhibitor avoided inhibitory loss but not excitatory gain. These results indicate that NO mediates inhibitory loss occurring from the pre‐ to early‐symptomatic stage of hSOD1 G93A mice. This work contributes new insights on ALS pathogenesis, recognizing synaptic re‐arrangement onto motoneurons as a mechanism favoring disease progression rather than as a protective homeostatic response against excitotoxic events.

Excitotoxicity

10.1111/j.1750-3639.2010.00417.x

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Dual neuroprotective pathways of a pro‐electrophilic compound via HSF‐1‐activated heat‐shock proteins and Nrf2‐activated phase 2 antioxidant response enzymes

Journal of Neurochemistry (2011)

Takumi Satoh Tayebeh Rezaie Masaaki Seki Carmen R. Sunico Takahito Tabuchi

Activation of the Keap1/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and consequent induction of phase 2 antioxidant enzymes is known to afford neuroprotection. Here, we present a series of novel electrophilic compounds that protect neurons via this pathway. Natural products, such as carnosic acid (CA), are present in high amounts in the herbs rosemary and sage as ortho-dihydroquinones, and have attracted particular attention because they are converted by oxidative stress to their active form (ortho-quinone species) that stimulate the Keap1/Nrf2 transcriptional pathway. Once activated, this pathway leads to the production of a series of antioxidant phase 2 enzymes. Thus, such dihydroquinones function as redox-activated 'pro-electrophiles'. Here, we explored the concept that related para-dihydroquinones represent even more effective bioactive pro-electrophiles for the induction of phase 2 enzymes without producing toxic side effects. We synthesized several novel para-hydroquinone-type pro-electrophilic compounds (designated D1 and D2) to analyze their protective mechanism. DNA microarray, PCR, and western blot analyses showed that compound D1 induced expression of heat-shock proteins (HSPs), including HSP70, HSP27, and DnaJ, in addition to phase 2 enzymes such as hemeoxygenase-1 (HO-1), NADP(H) quinine-oxidoreductase1, and the Na(+)-independent cystine/glutamate exchanger (xCT). Treatment with D1 resulted in activation of Nrf2 and heat-shock transcription factor-1 (HSF-1) transcriptional elements, thus inducing phase 2 enzymes and HSPs, respectively. In this manner, D1 protected neuronal cells from both oxidative and endoplasmic reticulum (ER)-related stress. Additionally, D1 suppressed induction of 78 kDa glucose-regulated protein (GRP78), an ER chaperone protein, and inhibited hyperoxidation of peroxiredoxin 2 (PRX2), a molecule that is in its reduced state can protect from oxidative stress. These results suggest that D1 is a novel pro-electrophilic compound that activates both the Nrf2 and HSF-1 pathways, and may thus offer protection from oxidative and ER stress.

KEAP1

10.1111/j.1471-4159.2011.07449.x

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Citations (57)

NOS Antagonism Using Viral Vectors as an Experimental Strategy: Implications for In Vivo Studies of Cardiovascular Control and Peripheral Neuropathies

Methods in molecular biology (2010)

Beihui Liu James Hewinson Haibo Xu Francisco Montero Carmen R. Sunico

10.1007/978-1-61737-964-2_15

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Evidence for endothelial nitric oxide as a negative regulator of Schwann cell dedifferentiation after peripheral nerve injury

Neuroscience Letters (2010)

Carmen R. Sunico Bernardo Moreno‐López

Endoneurium

Schwann cell

Peripheral nerve injury

Nerve Injury

10.1016/j.neulet.2010.01.024

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Evidence for a detrimental role of nitric oxide synthesized by endothelial nitric oxide synthase after peripheral nerve injury

Neuroscience (2008)

Carmen R. Sunico Federico Portillo David González‐Forero Sergey Kasparov Bernardo Moreno‐López

Reinnervation

Peripheral nerve injury

Nerve Injury

Endothelial NOS

Motor nerve

10.1016/j.neuroscience.2008.09.001

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Citations (21)

Papel del oxido nitrico en procesos de plasticidad neuronal en el sistema nervioso central y periferico del mamifero

Carmen R. Sunico

La lesion de un nervio periferico induce la sobre-expresion de la enzima oxido nitrico sintasa (Nos) en el nervio afectado. Este tipo de lesion, asi como ciertas enfermedades neurodegenerativas, cursan con una disminucion de la densidad sinaptica central junto con la expresion de novo y/o sobre-expresion de NOS neuronal (nNOS) en las motoneuronas. Dado que el oxido nitrico (NO) participa en numerosos fenomenos de plasticidad sinaptica, se podria sugerir un papel del NO en procesos de El principal objetivo de este estudio fue evaluar el papel del NO en la plasticidad neuronal del SNP y SMC en condiciones patofisiologicas. Tras la lesion del nervio hipogloso (XIIn) , la inhibicion cronica de la NOS endotelial (eNOS) asi como la inyeccion intraneural de un vector adenoviral dirigido a expresar un dominante negativo mutado, de la eNOS, aceleraron la recuperacion funcional de la union neuronuscular e incrementaron la regeneracion axonal, revelado por registros del potencial muscular de accion compuesto y por el marcaje retrogrado de las motoneuronas del nucleo hipogloso (HNM5) . En el SMC adulto, el aplastamiento del l o la transduccion de las H1'lNs con vectores adenovirales dirigidos a expresar nNOS, demostraron que el NO es necesario y suficiente para inducir una perdida de sinapsis excitadoras, y para inhibir la formacion de nuevas sinapsis mediante mecanismos dependientes de Capciclico y 5- nitrosilacion, respectivamente. Ademas, incubaciones de rodajas de tronco encefalico de rata postnatal in vitro con un donante de NO indujeron la retirada de botones sinapticos excitadores e inhibidores en las HMNs, mediante un mecanismo de accion paracrino/retrogrado por accion de la via CCs/PICa y dependiente de la actividad Rho kinasa. Adicionalmente, en un modelo murino de esclerosis lateral amiotrofica (Eta), las HYINs mostraron una perdida de botones sinapticos inhibidores dependiente de NO, y una ganancia de entradas e independiente de NO, revelado por microscopias confocal y

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S2.3 Detrimental role of endothelial nitric oxide in motor peripheral neuropathies in the adult rat

Autonomic Neuroscience (2009)

Carmen R. Sunico Bernardo Moreno‐López

Hypoglossal nerve

Hypoglossal nucleus

10.1016/j.autneu.2009.05.013

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