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Increased Oxidative Stress and Impaired Antioxidant Response in Lafora Disease

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Abstract

Lafora disease (LD, OMIM 254780, ORPHA501) is a fatal neurodegenerative disorder characterized by the presence of glycogen-like intracellular inclusions called Lafora bodies and caused, in the vast majority of cases, by mutations in either EPM2A or EPM2B genes, encoding respectively laforin and malin. In the last years, several reports have revealed molecular details of these two proteins and have identified several processes affected in LD, but the pathophysiology of the disease still remains largely unknown. Since autophagy impairment has been reported as a characteristic treat in both Lafora disease cell and animal models, and as there is a link between autophagy and mitochondrial performance, we sought to determine if mitochondrial function could be altered in those models. Using fibroblasts from LD patients, deficient in laforin or malin, we found mitochondrial alterations, oxidative stress and a deficiency in antioxidant enzymes involved in the detoxification of reactive oxygen species (ROS). Similar results were obtained in brain tissue samples from transgenic mice deficient in either the EPM2A or EPM2B genes. Furthermore, in a proteomic analysis of brain tissue obtained from Epm2b−/−mice, we observed an increase in a modified form of peroxiredoxin-6, an antioxidant enzyme involved in other neurological pathologies, thus corroborating an alteration of the redox condition. These data support that oxidative stress produced by an increase in ROS production and an impairment of the antioxidant enzyme response to this stress play an important role in development of LD.

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Abbreviations

CCCP :

carbonyl cyanide m-chlorophenylhydrazone

ER :

endoplasmic reticulum

LBs :

Lafora bodies

LD :

Lafora disease

2D-DIGE :

two-dimensional differential in gel electrophoresis

Prdx6 :

peroxiredoxin-6

ROS :

reactive oxygen species

VDAC2 :

voltage-dependent anion-selective channel protein 2

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Acknowledgments

This work was supported by grants from the Spanish Ministry of Education and Science (SAF2011-27442, BFU2011-22630), Fundació La Marató de TV3 (ref. 100130), EU-Funded FRAILOMIC-HEALTH.2012.2.1.1, TREAT-CMT IRDiRC consortium Research fellowship, Generalitat Valenciana (Prometeo 2009/051, Prometeo 2012/061) and an ACCI2012 action from CIBERER, an initiative of the Instituto de Salud Carlos III.

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Authors and Affiliations

  1. Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas (IBV-CSIC), C/Jaime Roig, 11, 46010, Valencia, Spain

    Carlos Romá-Mateo & Pascual Sanz

  2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain

    Carlos Romá-Mateo, Carmen Aguado, José Luis García-Giménez, Marta Seco-Cervera, Federico V. Pallardó, Erwin Knecht & Pascual Sanz

  3. Centro de Investigación Príncipe Felipe, Valencia, Spain

    Carmen Aguado & Erwin Knecht

  4. FIHCUV-INCLIVA, Valencia, Spain

    José Luis García-Giménez, Marta Seco-Cervera & Federico V. Pallardó

  5. Department of Physiology, School of Medicine and Dentistry, University of Valencia, Valencia, Spain

    José Luis García-Giménez, José Santiago Ibáñez-Cabellos, Marta Seco-Cervera & Federico V. Pallardó

  6. Sistemas Genómicos, Paterna, Spain

    José Santiago Ibáñez-Cabellos

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  1. Carlos Romá-Mateo
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Correspondence to Pascual Sanz.

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Carlos Romá-Mateo Carmen Aguado and José Luis García-Giménez contributed equally to this work.

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Romá-Mateo, C., Aguado, C., García-Giménez, J.L. et al. Increased Oxidative Stress and Impaired Antioxidant Response in Lafora Disease. Mol Neurobiol 51, 932–946 (2015). https://doi.org/10.1007/s12035-014-8747-0

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