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 Ca(2+) concentration ([Ca(2+)](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 Ca(2+) (Ca(V)) channel subunit Ca(V)α(2)δ1 in the plasma membrane enhancing Ca(V)1 channel-mediated Ca(2+) influx and [Ca(2+)](i), resulting in impaired mitochondrial function. Consequently, impairments in [Ca(2+)](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 Ca(V)α(2)δ1 subunits. Our findings may lay the foundation for a pharmacological treatment strategy for patients suffering from a combination of these diseases.