Amyotrophic lateral sclerosis patient antibodies label Ca²⁺ channel α₁ subunit

Abstract

Sporadic amyotrophic lateral sclerosis is an idiopathic human degenerative disease of spinal cord and brain motor neurons. Prior studies demonstrated that most patients with amyotrophic lateral sclerosis possess immunoglobulins that bind to purified L-type voltage-gated calcium channels, that titers of anti-voltage-gated calcium channel antibodies correlate with disease progression rates, and that amyotrophic lateral sclerosis patient-derived antibodies (ALS IgG) produce electrophysiological 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 calcium channel is now identified as the major voltage-gated calcium channel antigen to which ALS IgG binds. Additionally, the binding of an L-type voltage-gated calcium channel alpha 1 subunit-directed monoclonal antibody, which itself mimics the effects of ALS IgG on skeletal muscle voltage-gated calcium channel currents, is selectively prevented by preaddition of ALS IgG. Voltage-gated calcium channel-binding IgG from patients with Lambert-Eaton myasthenic syndrome appears to be differentiated from ALS IgG by the reactivity of the former to both alpha 1 and beta subunits of the calcium channel. These assays provide further evidence linking amyotrophic lateral sclerosis to an autoimmune process, and suggest one means to differentiate immunoglobulins from patients with amyotrophic lateral sclerosis from those of patients with another autoimmune disease expressing calcium channel antibodies.

Cytotoxicity of immunoglobulins from amyotrophic lateral sclerosis patients on a hybrid motoneuron cell line.

“…These data are consistent with the observation that ALS IgG selectively recognizes the VGCC a, subunit (35). However, although VSC 4.1 cells possess dihydropyridine-sensitive L-type VGCC binding sites, IgG-mediated cytotoxicity is dihydropyridine insensitive and apparently not mediated by L-type VGCCs.…”

Calcium Signaling Pathways Mediating Synaptic Potentiation Triggered by Amyotrophic Lateral Sclerosis IgG in Motor Nerve Terminals

“…Controversial evidence has been presented about an interaction between ALS-IgG and VDCCs (Ordonez and Sotelo, 1989;Kimura et al, 1994;R. G. Smith et al, 1994;Arsac et al, 1996) and their capability to modify Ca 2ϩ currents.…”

Expression of a Cu,Zn superoxide dismutase typical of familial amyotrophic lateral sclerosis induces mitochondrial alteration and increase of cytosolic Ca2+ concentration in transfected neuroblastoma SH‐SY5Y cells

“…Fax: (39) (6) 72594311. E-mail: rotilio@utovrm.it seems to play a central role among the mechanisms presumably involved in the pathogenesis of ALS; low levels of Ca 2+ binding proteins have been detected in human motoneurons [6,7]; increased Ca 2+ concentration is present in ALS patients [7] and many sporadic ALS patients possess serum antibodies to both L-type and P-type calcium channels [4,8] which are able to increase calcium entry in a motoneuron cell line [9]. Mitochondrial damage seems also to be involved, since alterations of these organelles have been reported in transgenic mice overexpressing mutant SOD [10] and changes in the activities of the mitochondrial electron transport chain complex I have been reported in FALS patients [3].…”