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KATP Channel Expression and Genetic Polymorphisms Associated with Progression and Survival in Amyotrophic Lateral Sclerosis

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Abstract

The ATP-sensitive potassium (KATP) channel directly regulates the microglia-mediated inflammatory response following CNS injury. To determine the putative role of the KATP channel in amyotrophic lateral sclerosis (ALS) pathology, we investigated whether ALS induces changes in KATP channel expression in the spinal cord and motor cortex. We also characterized new functional variants of human ABCC8, ABCC9, KCNJ8, and KCNJ11 genes encoding for the KATP channel and analyzed their association with ALS risk, rate of progression, and survival in a Spanish ALS cohort. The expression of ABCC8 and KCNJ8 genes was enhanced in the spinal cord of ALS samples, and KCNJ11 increased in motor cortex of ALS samples, as determined by real-time polymerase chain reaction. We then sequenced the exons and regulatory regions of KATP channel genes from a subset of 28 ALS patients and identified 50 new genetic variants. For the case-control association analysis, we genotyped five selected polymorphisms with predicted functional relevance in 185 Spanish ALS (134 spinal ALS and 51 bulbar ALS) patients and 493 controls. We found that bulbar ALS patients presenting the G/G genotype of the rs4148646 variant of ABCC8 and the T/T genotype of the rs5219 variant of KCNJ11 survived longer than other ALS patients presenting other genotypes. Also, the C/C genotype of the rs4148642 variant of ABCC8 and the T/C genotype of the rs148416760 variant of ABCC9 modified the progression rate in spinal ALS patients. Our results suggest that the KATP channel plays a role in the pathophysiological mechanisms of ALS.

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Acknowledgements

We are indebted to the Neurological Tissue Bank of the IDIBAPS Biobank and especially to Dr. Hellen Gelpi for the human postmortem brain samples and data procurement. The authors also thank to the Spanish National DNA Bank for providing control samples and to Alan Lopez-Lopez for helping in data collection.

Funding

This research was supported by grants 2014SGR1115 and RD10-1-0072 from the Generalitat de Catalunya (Spain). MJR was supported by grant SAF2017-88076-R from the Spanish Ministry of Economy, Industry and Competitivity, the Spanish National Research Agency, and the European Regional Development Fund. JG and MS were supported by grants FIS-FEDER PI16/01673 and FIS-FEDER PI17/00789, respectively, both of them from the Spanish Ministry of Health.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Institut de Neurociències, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat de Barcelona, Barcelona, Spain

    José M. Vidal-Taboada, Marco Pugliese, Nicole Mahy & Manuel J. Rodríguez

  2. ALS Unit, Department of Neurology, Hospital Universitari Vall d’Hebron – VHIR, Universitat Autònoma de Barcelona, Barcelona, Spain

    Maria Salvadó & Josep Gámez

  3. Unitat de Bioquímica i Biologia Molecular, Department of Biomedicina, Facultat de Medicina, UB, c/ Casanova 143, E-08036, Barcelona, Spain

    Manuel J. Rodríguez

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  1. José M. Vidal-Taboada
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  2. Marco Pugliese
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  3. Maria Salvadó
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  4. Josep Gámez
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Correspondence to Manuel J. Rodríguez.

Ethics declarations

The local IRBs at the Vall d’Hebron Research Institute, the DIBAPS Biobank, and the Spanish National DNA Bank approved the protocols of this study. It was conducted according to the principles set out in the Declaration of Helsinki. All patients and/or close relatives gave their written informed consent to participation in the study in paper format, and a blood sample for genetic analysis was obtained from all of them. CNS tissue donors gave their informed written consent for the use of CNS tissue for research purposes. The categorization of ALS patients was performed according to their clinical features (familial or sporadic ALS forms, bulbar or spinal or respiratory onset, rate of progression, and survival time). No experiments with animals were performed in this study.

Conflict of Interest

MP, NM, and MJR applied for a PCT application “Diazoxide for use in the treatment of amyotrophic lateral sclerosis (ALS)” (Application number PCT/EP2011/064061). The other authors declare that they have no conflict of interest.

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Vidal-Taboada, J.M., Pugliese, M., Salvadó, M. et al. KATP Channel Expression and Genetic Polymorphisms Associated with Progression and Survival in Amyotrophic Lateral Sclerosis. Mol Neurobiol 55, 7962–7972 (2018). https://doi.org/10.1007/s12035-018-0970-7

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