Reduction of P/Q-type calcium channels in the postmortem cerebellum of paraneoplastic cerebellar degeneration with Lambert-Eaton myasthenic syndrome

Ann Neurol. 2003 Jan;53(1):21-8. doi: 10.1002/ana.10392.

Abstract

The aim of this study was to clarify whether autoimmunity against P/Q-type voltage-gated calcium channels (VGCCs) in the cerebellum was associated with the pathogenesis of paraneoplastic cerebellar degeneration (PCD) with Lambert-Eaton myasthenic syndrome (LEMS). We used human autopsy cerebellar tissues from three PCD-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 125I-omega-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-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 VGCCs measured by immunoprecipitation assay were increased in PCD-LEMS patients. We analysed cerebellar specimens by autoradiography using (125)I-omega-conotoxin MVIIC, which specifically binds to P/Q-type VGCCs. In PCD-LEMS cerebellum, the toxin binding sites of P/Q-type VGCCs were markedly reduced compared with controls, especially in the molecular layer, which is the richest area of P/Q-type VGCCs in the normal cerebellum. This suggests that P/Q-type VGCCs of the cerebellar molecular layer is the immunological target in developing PCD-LEMS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Autoantibodies / immunology*
  • Autoradiography
  • Calcium Channels, N-Type / immunology*
  • Calcium Channels, N-Type / metabolism*
  • Cerebellar Ataxia / immunology
  • Cerebellar Ataxia / metabolism
  • Cerebellar Ataxia / pathology
  • Cerebellum / immunology*
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • Elapid Venoms / metabolism
  • Elapid Venoms / pharmacology
  • Female
  • Humans
  • Iodine Radioisotopes
  • Lambert-Eaton Myasthenic Syndrome / immunology*
  • Lambert-Eaton Myasthenic Syndrome / metabolism
  • Lambert-Eaton Myasthenic Syndrome / pathology
  • Male
  • Paraneoplastic Cerebellar Degeneration / immunology*
  • Paraneoplastic Cerebellar Degeneration / metabolism
  • Paraneoplastic Cerebellar Degeneration / pathology
  • omega-Conotoxins / metabolism
  • omega-Conotoxins / pharmacology

Substances

  • Autoantibodies
  • Calcium Channels, N-Type
  • Elapid Venoms
  • Iodine Radioisotopes
  • omega-Conotoxins
  • voltage-dependent calcium channel (P-Q type)
  • dendrotoxin