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.

Cerebellar long-term depression and auto-immune target of auto-antibodies: the concept of LTDpathies

“…During the last two decades, experimental and clinical studies have established the pathological roles of autoantibodies against ion channels and synaptic receptors in limbic encephalitis [1][2][3][4][5]. Although auto-antibodies that target ion channels and synaptic machineries have been documented also in immune-mediated cerebellar ataxias (IMCAs), the types of auto-antibodies involved in IMCAs are different from those observed in limbic auto-immune encephalitis [6]. Anti-glutamate receptors, anti-GABA receptors and anti-leucine-rich glioma-inactivated 1(LGI1) antibodies (Abs) are rarely observed in IMCAs, whereas the association of CAs with anti-GAD65, anti-voltagegated Ca channel (VGCC), anti-metabotropic glutamate receptor type 1 (mGluR1), and anti-glutamic receptor delta (GluR delta) Abs has been documented [7][8][9][10][11][12].…”

“…Anti-glutamate receptors, anti-GABA receptors and anti-leucine-rich glioma-inactivated 1(LGI1) antibodies (Abs) are rarely observed in IMCAs, whereas the association of CAs with anti-GAD65, anti-voltagegated Ca channel (VGCC), anti-metabotropic glutamate receptor type 1 (mGluR1), and anti-glutamic receptor delta (GluR delta) Abs has been documented [7][8][9][10][11][12]. Especially, auto-antibodies against VGCC, mGluR and GluR delta are characteristically found in IMCAs, but not in auto-immune limbic encephalitis [6,13]. These target molecules are involved in molecular cascades that induce long-term synaptic depression (LTD) of synaptic transmissions between parallel fibers (PFs) and Purkinje cells (PCs), a crucial form of synaptic plasticity in the cerebellum [6,13].…”

“…Especially, auto-antibodies against VGCC, mGluR and GluR delta are characteristically found in IMCAs, but not in auto-immune limbic encephalitis [ 6 , 13 ]. These target molecules are involved in molecular cascades that induce long-term synaptic depression (LTD) of synaptic transmissions between parallel fibers (PFs) and Purkinje cells (PCs), a crucial form of synaptic plasticity in the cerebellum [ 6 , 13 ].…”

LTDpathies: a Novel Clinical Concept

“…In IMCAs, various synaptic proteins, such as glutamic acid decarboxylase 65 (GAD65), voltage-gated Ca channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluR delta), are targets of auto-immunity [ 14 – 16 ]. Although the auto-immunity and clinical profiles vary enormously among CAs associated with anti-VGCC, anti-mGluR1, and anti-GluR delta antibodies (Abs), these three subtypes show the common clinical features of good prognosis with no or mild cerebellar atrophy in non-paraneoplastic syndrome [ 13 , 17 ], suggesting functional cerebellar disorders without or with weak neuronal death. Notably, anti-VGCC, anti-mGluR1, and anti-GluR delta Abs are preferentially found in IMCAs and not in other autoimmune neurological conditions such as autoimmune limbic encephalitis [ 17 ].…”

“…Although the auto-immunity and clinical profiles vary enormously among CAs associated with anti-VGCC, anti-mGluR1, and anti-GluR delta antibodies (Abs), these three subtypes show the common clinical features of good prognosis with no or mild cerebellar atrophy in non-paraneoplastic syndrome [ 13 , 17 ], suggesting functional cerebellar disorders without or with weak neuronal death. Notably, anti-VGCC, anti-mGluR1, and anti-GluR delta Abs are preferentially found in IMCAs and not in other autoimmune neurological conditions such as autoimmune limbic encephalitis [ 17 ]. This preferential distribution might reflect vulnerability in the functional roles of these auto-antigens among elementary cerebellar functions.…”