IgGs from patients with amyotrophic lateral sclerosis and diabetes target Ca_Vα₂δ1 subunits impairing islet cell function and survival

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⁺ (Ca_V) channel subunit Ca_Vα₂δ1 in the plasma membrane enhancing Ca_V1 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 Ca_Vα₂δ1 subunits. Our findings may lay the foundation for a pharmacological treatment strategy for patients suffering from a combination of these diseases.