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Title:
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Protein oxidation in Huntington disease affects energy production and vitamin B6 metabolism
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Author:
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Sorolla Bardají, Maria Alba; Rodríguez Colman, Maria José; Tamarit Sumalla, Jordi; Ortega, Zaira; Lucas, José J.; Ferrer, Isidre; Ros Salvador, Joaquim; Cabiscol Català, Elisa
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Notes:
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Huntington disease (HD) is an inherited neurodegenerative disorder that initially affects the striatum and
progressively the cortex. Oxidative stress in HD has been described as important to disease progression. In this
study, protein carbonylation, used as a marker of protein oxidation, was analyzed in human brain striatum. A
comparison of HD samples tomatched controls identified 13 carbonylated proteins, including enzymes involved
in the glycolytic pathway and mitochondrial proteins related to ATP production. Oxidation of the mitochondrial
enzymes resulted in decreased catalytic activity, in good agreement with the energy deficiency observed in HD.
Wealso found carbonylation of pyridoxal kinase and antiquitin 1, both involved in themetabolismof pyridoxal 5-
phosphate, the active formof vitamin B6. The Tet/HD94 conditionalmousemodel allowed us to demonstrate that
increased carbonylation in striatum is dependent on mutant huntingtin expression. As in humans, pyridoxal
kinase showed decreased levels and was highly carbonylated in the gene-on mice; these modifications were
reverted in the gene-offmice. Wehypothesize that both pyridoxal kinase and antiquitin 1 oxidation could result
in decreased pyridoxal 5-phosphate availability necessary as a cofactor in transaminations, synthesis of
glutathione, and synthesis of GABA and dopamine, two neurotransmitters that play a key role in HD pathology.
This work was supported by Grants BFU2007-66249 and CSD2007- 20 Consolider Ingenio 2010 from the Ministerio de Ciencia e Innovación (Spain) and SGR2009-00196 from the Generalitat de Catalunya. M.A. Sorolla and M.J. Rodriguez-Colman are recipients of Ph.D. fellowships from the Ministerio de Ciencia e Innovación. Work by the J.J. Lucas team was supported by the Ministerio de Ciencia e Innovación, CiberNed, Comunidad Autónoma de Madrid, and Fundación Ramón Areces. |
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Subject(s):
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-Huntington disease
-Oxyproteome
-Oxidative stress |
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Rights:
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(c) Elsevier, 2010
info:eu-repo/semantics/restrictedAccess |
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Document type:
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article
publishedVersion |
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Published by:
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Elsevier
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