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

1
Department of Medical Education, Tokyo Medical University, Tokyo 160-0023, Japan
2
French Reference Center on Paraneoplastic Neurological Syndromes, Hospices Civils de Lyon, Hôpital Neurologique, 69677 Bron, France
3
Institut NeuroMyoGene INSERM U1217/CNRS UMR 5310, Université de Lyon, Université Claude Bernard Lyon 1, 69372 Lyon, France
4
Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8511, Japan
5
Unité des Ataxies Cérébelleuses, Service de Neurologie, Médiathèque Jean Jacquy, CHU-Charleroi, 6000 Charleroi, Belgium
6
Service des Neurosciences, University of Mons, 7000 Mons, Belgium
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(14), 4936; https://doi.org/10.3390/ijms21144936
Received: 31 May 2020 / Revised: 7 July 2020 / Accepted: 9 July 2020 / Published: 13 July 2020
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. View Full-Text
Keywords: cerebellar ataxias; immune-mediated cerebellar ataxias; autoantibodies; anti-voltage-gated Ca channel antibody; anti-metabotropic glutamate receptor 1 antibody; anti-GAD 65 antibody cerebellar ataxias; immune-mediated cerebellar ataxias; autoantibodies; anti-voltage-gated Ca channel antibody; anti-metabotropic glutamate receptor 1 antibody; anti-GAD 65 antibody
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Mitoma, H.; Honnorat, J.; Yamaguchi, K.; Manto, M. Fundamental Mechanisms of Autoantibody-Induced Impairments on Ion Channels and Synapses in Immune-Mediated Cerebellar Ataxias. Int. J. Mol. Sci. 2020, 21, 4936.

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