3-Nitropropionic Acid as a Tool to Study the Mechanisms Involved in Huntington’s Disease: Past, Present and Future

Túnez, Isaac; Tasset, Inmaculada; Cruz, Verónica Pérez de la; Santamarı́a, Abel

doi:10.3390/molecules15020878

Cited by 173 publications

(100 citation statements)

References 264 publications

(318 reference statements)

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“…SdhAF1 is a 115-amino acid soluble The remaining small molecules are demonstrated to be inhibitors. Inhibition of complex II by any of these small molecules, except citrate, is associated with neurodegenerative symptoms in humans or in animal models, and malate and 3-nitropropionate are commonly used in animal models of Huntington disease (25,26). This figure was originally published in Ref.…”

Section: Aberrant Complex II Activity Associated With Neurodegenerationmentioning

confidence: 99%

“…Complex II Inhibition Associated with NeurodegenerationCompetitive inhibition of succinate oxidation in human and animal models results in the specific loss of striatal neurons and symptoms reminiscent of a large subset of those associated with Huntington disease (25,26). It is well established that molecules that resemble the dicarboxylate substrate succinate (Fig.…”

Section: Aberrant Complex II Activity Associated With Neurodegenerationmentioning

confidence: 99%

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Structural Basis for Malfunction in Complex II

Iverson

Maklashina

Cecchini

2012

Journal of Biological Chemistry

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Complex II couples oxidoreduction of succinate and fumarate at one active site with that of quinol/quinone at a second distinct active site over 40 Å away. This process links the Krebs cycle to oxidative phosphorylation and ATP synthesis. The pathogenic mutation or inhibition of human complex II or its assembly factors is often associated with neurodegeneration or tumor formation in tissues derived from the neural crest. This brief overview of complex II correlates the clinical presentations of a large number of symptom-associated alterations in human complex II activity and assembly with the biochemical manifestations of similar alterations in the complex II homologs from Escherichia coli. These analyses provide clues to the molecular basis for diseases associated with aberrant complex II function.Over the past 6 decades, complex II (succinate dehydrogenase, succinate:quinone oxidoreductase (SQR) 3 ) has been at the forefront in the discovery of redox cofactors involved in bioenergetics. Helmut Beinert noted that in the 1950s-1960s, complex II was instrumental in the discovery of covalently bound flavin, tightly bound iron, and acid-labile sulfur associated with Fe-S clusters and bound ubiquinone of the mitochondrial respiratory chain (1). In 1995, a mutation of human complex II was the first report of a nuclear gene mutation shown to cause a mitochondrial respiratory chain deficiency (2). More recently, germ-line mutations in complex II have been found to be associated with hereditary tumors, suggesting that complex II genes may act as tumor suppressors (3).Complex II enzymes ( Fig. 1A) are heterotetramers containing two soluble subunits (SdhA (flavoprotein) and SdhB (Fe-S protein)) and two integral membrane subunits (SdhC and SdhD). This architecture houses two distinct active sites, and the coordinated catalysis at these sites links two key biological pathways, i.e. succinate oxidation to the Krebs cycle and quinone reduction to the electron transport chain. The SdhA subunit harbors a covalently attached FAD redox moiety and the dicarboxylate-binding site (Fig. 1B), where succinate is oxidized to fumarate. The product protons of this oxidation are transferred to bulk solvent, and fumarate acts as the next substrate in the Krebs cycle. The product electrons are transferred over 40 Å via three Fe-S clusters in the SdhB protein. These electrons act as co-substrates at the second active site, located at the interface of the integral membrane subunits. At this quinonereducing site (Fig. 1C), 2H ϩ and 2eϪ reduce ubiquinone to ubiquinol. The resultant quinol pool supports ATP synthesis by oxidative phosphorylation.The complex II superfamily contains both SQRs and quinol: fumarate reductases (QFRs). QFRs are enzymes that are kinetically poised to catalyze quinol oxidation and fumarate reduction as part of anaerobic electron transport chains. Both enzymes have evolved to function optimally in the physiological niche in which they are expressed. SQR and QFR are capable of functionally replacing each other in vivo in E...

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Section: Aberrant Complex II Activity Associated With Neurodegenerationmentioning

confidence: 99%

Section: Aberrant Complex II Activity Associated With Neurodegenerationmentioning

confidence: 99%

Structural Basis for Malfunction in Complex II

Iverson

Maklashina

Cecchini

2012

Journal of Biological Chemistry

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“…The symptoms of Huntington's disease have been described as early as the fourteenth century, when it was also known as Saint Vitus's dance or dancing plague (Tunez et al, 2010). The disease was first described by Charles Waters as a convulsive disorder, but in 1872 George Huntington formally described it for the first time and referred to it as a hereditary chorea (Huntington, 1872).…”

Section: Xenotransplantation In Huntington's Diseasementioning

confidence: 99%

The Use of Xenotransplantation in Neurodegenerative Diseases: A Way to Go?

Lévèque¹,

Fink²,

Rossignol³

et al. 2012

Xenotransplantation

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“…El efecto desencadenado por el ácido 3-nitropropiónico obedece a su acción inhibidora de la succinato deshidrogenasa, enzima presente en el complejo II de la cadena de transporte electrónico mitocondrial y en el ciclo de Krebs. La acción de este inhibidor suicida causa un descenso en la síntesis de ATP y un incremento en la producción de ERO, con la consecuente presencia de un intenso daño oxidativo y muerte neuronal (11)(12)(13).…”

Section: Introductionunclassified

Antioxidant effect of oleic acid and hydroxytyrosol in an experimental model similar to Huntington's disease

Alconchel¹,

Santamarı́a²,

Túnez³

2014

Actual. Med.

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Efecto antioxidante del ácido oleico e hidroxitirosol en un modelo experimental similar a la enfermedad de Huntington ResumenLos radicales libres juegan un papel fundamental en la alteración neuronal que tiene lugar en enfermedades neurodegenerativas y en el envejecimiento cerebral. Se ha asociado la dieta Mediterránea con la reducción del riesgo de padecer enfermedades neurodegenerativas. Objetivos. Este estudio fue diseñado para probar si el ácido oleico y el hidroxitirosol, componentes del aceite de oliva virgen-extra, ejercen un efecto antioxidante protector en el cerebro ante el estrés oxidativo inducido por el ácido 3-nitropropiónico. Métodos. El ácido 3-nitropropiónico se administró intraperitonealmente a una dosis de 20 mg/kg de peso durante cuatro días consecutivos. El ácido oleico (con una dosis del 4% de calorías ingeridas diariamente por el animal) y el hidroxitirosol (2,5 mg/kg de peso en solución acuosa) se administraron durante 14 días a ratas Wistar. Resultados. El ácido 3-nitropropiónico causó un aumento de la peroxidación lipídica y de la actividad de la glutatión peroxidasa, y una reducción en la concentración de glutatión reducido. Los resultados obtenidos además demuestran que el ácido oleico y el hidroxitirosol reducen los niveles de los productos de peroxidación lipídica y bloquean el agotamiento del glutatión reducido en el cerebro tras la administración de ácido 3-nitropropiónico. Conclusión. Tanto el ácido oleico como el hidroxitirosol actúan como potentes antioxidantes frente al estrés oxidativo inducido por el ácido 3-nitropropiónico. AbstractFree radicals play an important role in neuronal alterations during the progression of neurodegenerative disorders and brain aging. Mediterranean-style diet has been associated to a reduction in the risk to develop neurodegenerative disorders. Objectives. This study was designed to test whether oleic acid and hydroxytyrosol, both components of extra-virgin olive oil, exert an antioxidant and protective effect in the brain subjected to oxidative stress induced by 3-nitropropionic acid. Methods. 3-Nitropropionic acid was administered intraperitoneally to animals at a dose of 20 mg/kg for 4 consecutive days. Oleic acid (given at a dose equivalent to 4% of the calories ingested every day per animal) and hydroxytyrosol (2,5 mg/kg, dissolved in aqueoussolution) were administered during 14 consecutive days to Wistar rats. Results. 3-Nitropropionic acid caused increased levels of lipid peroxidation and glutathione peroxidase activity, and a depletion in the concentration of reduced glutathione. Our findings also demonstrate that oleic acid and hydroxytyrosol reduce the levels of lipid peroxidation and prevent the depletion of reduced glutathione in the brain induced by the administration of 3-nitropropionic acid. Conclusion. Both oleic acid and hydroxytyrosol act as potent antioxidants against the oxidative damage induced by 3-nitropropionic acid.

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3-Nitropropionic Acid as a Tool to Study the Mechanisms Involved in Huntington’s Disease: Past, Present and Future

Cited by 173 publications

References 264 publications

Structural Basis for Malfunction in Complex II

Structural Basis for Malfunction in Complex II

The Use of Xenotransplantation in Neurodegenerative Diseases: A Way to Go?

Antioxidant effect of oleic acid and hydroxytyrosol in an experimental model similar to Huntington's disease

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