한빛사 논문
POSTECH, Karolinska Institutet, Nanyang Technological University, University of Miami
Yue Shia,1,2, Kyoung Sun Parkb,1, Seung Hyun Kimc, Jia Yua, Kaixuan Zhaoa, Lina Yua, Ki Wook Ohc, Kayoung Leeb, Jaeyoon Kimb, Kanchan Chaggard, Yuxin Lie, Annette C. Dolphind, William A. Catterallf,2, Sung Ho Ryub, Shao-Nian Yanga,e,2,3, and Per-Olof Berggrena,b,g,h,2,3
a The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden; b Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 37673, Korea; c Department of Neurology, Hanyang University Hospital, Seoul 04763, Korea; d Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom; e National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China; f Department of Pharmacology, School of Medicine, University of Washington, Seattle, WA 98195-7280; g Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637553; and h Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136
1 Y.S. and K.S.P. contributed equally to this work.
2 To whom correspondence may be addressed.
3 S.-N.Y. and P.-O.B. contributed equally to this work.
Abstract
Patients with amyotrophic lateral sclerosis (ALS) often show hallmarks of type 2 diabetes mellitus (T2DM). However, the causal link between ALS and T2DM has remained a mystery. We now demonstrate that 60% of ALS patients with T2DM (ALS-T2DM) have sera that exaggerated K+-induced increases in cytosolic free Ca2+ concentration ([Ca2+]i) in mouse islet cells. The effect was attributed to the presence of pathogenic immunoglobulin Gs (IgGs) in ALS-T2DM sera. The pathogenic IgGs immunocaptured the voltage-dependent Ca2+ (CaV) channel subunit CaVα2δ1 in the plasma membrane enhancing CaV1 channel-mediated Ca2+ influx and [Ca2+]i, resulting in impaired mitochondrial function. Consequently, impairments in [Ca2+]i dynamics, insulin secretion, and cell viability occurred. These data reveal that patients with ALS-T2DM carry cytotoxic ALS-T2DM-IgG autoantibodies that serve as a causal link between ALS and T2DM by immunoattacking CaVα2δ1 subunits. Our findings may lay the foundation for a pharmacological treatment strategy for patients suffering from a combination of these diseases.
amyotrophic lateral sclerosis, calcium channel, cytosolic free Ca2+ concentration, diabetes, immunoglobulin
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