Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2019 Dec 11. pii: 201911956. doi: 10.1073/pnas.1911956116. [Epub ahead of print]

IgGs from patients with amyotrophic lateral sclerosis and diabetes target CaVα2δ1 subunits impairing islet cell function and survival.

Author information

1
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden; yue.shi@ki.se wcatt@uw.edu shao-nian.yang@ki.se per-olof.berggren@ki.se.
2
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 37673, Korea.
3
Department of Neurology, Hanyang University Hospital, Seoul 04763, Korea.
4
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden.
5
Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom.
6
National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
7
Department of Pharmacology, School of Medicine, University of Washington, Seattle, WA 98195-7280; yue.shi@ki.se wcatt@uw.edu shao-nian.yang@ki.se per-olof.berggren@ki.se.
8
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637553.
9
Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136.

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.

KEYWORDS:

amyotrophic lateral sclerosis; calcium channel; cytosolic free Ca2+ concentration; diabetes; immunoglobulin

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center