Antibodies from ALS patients inhibit dopamine release mediated by L-type calcium channels

Objective: To examine the presence of anti-L-type calcium channel antibodies in the serum of ALS patients. Background: Autoimmunity has been hypothesized as one of the mechanisms underlying the pathogenesis of sporadic ALS. Previous studies reported that sera from patients with sporadic ALS contain antibodies against voltage-gated calcium channels (L-type and P-type), but others do not support these findings. Methods: Regulated secretion of tritiated dopamine ([H-3]DA) in PC12 cells is mediated exclusively by calcium entry through L-type calcium channels. To examine whether purified ALS immunoglobulin G (IgG) inhibits [H-3]DA release by interfering with calcium entry through L-type calcium channels, evoked release in PC12 cells was determined in the presence of ALS IgG. This functional assay provides a sensitive way to examine L-type calcium channel interaction with IgG from ALS patients. Results: A significant inhibition of depolarization-evoked [H-3]DA release (32 +/- 4%) was observed by purified IgG from ALS patients compared with control subjects (11 +/- 2%; p < 0.01). Significant inhibition by IgG occurred in 79% (15/19) of the ALS patients compared with only 29% (5/17) in the control group (p < 0.01). The level of calcium channel inhibition by ALS IgG correlated positively with disease duration (r = 0.68; p < 0.01) and correlated negatively with age (r = -0.48; p < 0.05). Conclusions: These results confirm the presence of antibodies against the L-type calcium channel in the majority of sera from ALS patients, supporting their role in the pathogenesis of ALS.