Fundamental Mechanisms of Autoantibody-Induced Impairments on Ion Channels and Synapses in Immune-Mediated Cerebellar Ataxias.

Abstract

In the last years, different kinds of limbic encephalitis associated with autoantibodies against ion channels and synaptic receptors have been described. Many studies have demonstrated that such autoantibodies induce channel or receptor dysfunction. The same mechanism is discussed in immune-mediated cerebellar ataxias (IMCAs), but the pathogenesis has been less investigated. The aim of the present review is to evaluate what kind of cerebellar ion channels, their related proteins, and the synaptic machinery proteins that are preferably impaired by autoantibodies so as to develop cerebellar ataxias (CAs). The cerebellum predictively coordinates motor and cognitive functions through a continuous update of an internal model. These controls are relayed by cerebellum-specific functions such as precise neuronal discharges with potassium channels, synaptic plasticity through calcium signaling pathways coupled with voltage-gated calcium channels (VGCC) and metabotropic glutamate receptors 1 (mGluR1), a synaptic organization with glutamate receptor delta (GluRδ), and output signal formation through chained GABAergic neurons. Consistently, the association of CAs with anti-potassium channel-related proteins, anti-VGCC, anti-mGluR1, and GluRδ, and anti-glutamate decarboxylase 65 antibodies is observed in IMCAs. Despite ample distributions of AMPA and GABA receptors, however, CAs are rare in conditions with autoantibodies against these receptors. Notably, when the autoantibodies impair synaptic transmission, the autoimmune targets are commonly classified into three categories: release machinery proteins, synaptic adhesion molecules, and receptors. This physiopathological categorization impacts on both our understanding of the pathophysiology and clinical prognosis.

• Authors: Hiroshi Mitoma, Jerome Honnorat, Kazuhiko Yamaguchi, Mario Manto
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 14 (Jul 13 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32668612 (Publication Type: Journal Article, Review)

Chemical References

• Autoantibodies
• Autoantigens
• Ion Channels
• Nerve Tissue Proteins
• Neural Cell Adhesion Molecules
• Neurotransmitter Agents

Topics

• Animals
• Antigen-Antibody Reactions
• Autoantibodies (immunology)
• Autoantigens (immunology, metabolism)
• Autoimmune Diseases of the Nervous System (immunology, metabolism)
• Cerebellar Ataxia (immunology, metabolism)
• Cerebellum (metabolism)
• Humans
• Ion Channels (antagonists & inhibitors, immunology, metabolism)
• Nerve Tissue Proteins (immunology, metabolism)
• Neural Cell Adhesion Molecules (metabolism)
• Neuronal Plasticity
• Neurotransmitter Agents (metabolism)
• Protein Transport
• Purkinje Cells (metabolism)
• Synapses (immunology, metabolism)