AMYOTROPHIC-LATERAL-SCLEROSIS PATIENT ANTIBODIES LABEL CA2+ CHANNEL ALPHA(1) SUBUNIT

Sporadic amyotrophic lateral sclerosis is an idiopathic human degenera tive disease of spinal cord and brain motor neurons. Prior studies dem onstrated that most patients with amyotrophic lateral sclerosis posses s immunoglobulins that bind to purified L-type voltage-gated calcium c hannels, that titers of anti-voltage-gated calcium channel antibodies correlate with disease progression rates, and that amytrophic lateral sclerosis patient-derived antibodies (ALS IgG) produce electrophysiolo gical changes in the function of voltage-gated calcium channels. Using Western transfer immunoblots and enzyme-linked immunosorbent assays, the calcium ionophore-forming alpha(1) subunit of the voltage-gated ca lcium channel is now identified as the major voltage-gated calcium cha nnel antigen to which ALS IgG binds. Additionally, the binding of an L -type voltage-gated calcium channel alpha(1) subunit-directed monoclon al antibody, which itself mimics the effects of ALS IgG on skeletal mu scle voltage-gated calcium channel currents, is selectively prevented by preaddition of ALS IgG. Voltage-gated calcium channel-binding IgG f rom patients with Lambert-Eaton myasthenic syndrome appears to be diff erentiated from ALS IgG by the reactivity of the former to both alpha( 1) and beta subunits of the calcium channel. These assays provide furt her evidence linking amyotrophic lateral sclerosis to an autoimmune pr ocess, and suggest one means to differentiate immunoglobulins from pat ients with amyotrophic lateral sclerosis from those of patients with a nother autoimmune disease expressing calcium channel antibodies.