Analysis of the P/Q-type calcium channel in autopsied patients with paraneoplastic cerebellar degeneration (PCD) and Lambert-Eaton myasthenic syndrome (LEMS)

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The aim of this study was to clarify whether autoimmunity against P/Q-type voltage-gated calcium channels (VGCC) in the cerebellum was associated with the pathogenesis of paraneoplastic cerebellar degeneration (PCD) with Lambert-Eaton myasthenic syndrome (LEMS). We used human cerebellar tissues obtained at autopsy from three PCD with LEMS patients and six other disease patients including one with LEMS as the controls. We compared cerebellar P/Q-type VGCC in these patients and controls for the amount and ratio of autoantibody-channel complex using an _<125>I-w-conotoxin MVIIC binding assay with Scatchard analysis, and their distribution using autoradiography. The quantity of cerebellar P/Q-type VGCC measured by Scatchard analysis were reduced in PCD with LEMS patients (63.0±7.0 fmol/mg, n=3), compared with the controls (297.8±38.9 fmol/mg, n=6). The ratio of autoantibody-VGCC complexes to total P/Q-type VGCC measured by immunoprecipitation assay were increased in PCD-LEMS patients. We analysed the autoradiographic image of cerebellar specimens using ^<125>I-ω-conotoxin MVIIC, which specifically binds to P/Q-type VGCC. In PCD-LEMS cerebellum, the toxin binding sites of P/Q-type VGCC were markedly reduced compared to control specimens, especially in the molecular layer which is the richest area of P/Q-type VGCC in the normal cerebellum. These results suggest that P/Q-type VGCC of the cerebellar molecular layer is the immunological target in developing PCD with LEMS.