SCIENTISTS PUBLISH NEW FINDINGS ON AUTOANTIBODIES TARGETING SYNAPTIC PROTEINS
New findings on autoantibodies targeting synaptic proteins have been recently published in Neuron and BRAIN journals by researchers from the Institute of Neurosciences and IDIBAPS. Both articles have been leaded by the team of Josep Dalmau in collaboration with researchers from the Neurophysiology group, David Soto and Xavier Gasull, and the group of Christian Geis in the Jena University Hospital (Germany). The paper entitled ‘LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory’ was published in BRAIN 2018 and focus on the effects of patient-derived immunoglobulin G (IgG) antibodies against Leucine-rich glioma-inactivated 1 (LGI1) protein. LGI1 forms a trans-synaptic complex with two proteins – ADAM23 and ADAM22 –, that interact presynaptically with Kv1.1 potassium channel and postsynaptically with AMPA receptors, respectively. Antibodies disrupt the interaction of LGI1 with these proteins and produce a decrease of synaptic levels of Kv1.1 and AMPA receptors, causing an increase in hippocampal neuronal excitability and glutamatergic transmission and severe impairment of long-term potentiation. Overall, these findings demonstrate that patient-derived IgG disrupt presynaptic and postsynaptic LGI1 signaling, causing neuronal hyperexcitability, decreased plasticity, and reversible memory deficits.
In a second paper published in Neuron (Human Autoantibodies against the AMPA Receptor Subunit GluA2 Induce Receptor Reorganization and Memory Dysfunction), the same authors demonstrate how specific autoantibodies found in patients with autoimmune encephalitis react against a specific subunit (GluA2) of the neuronal AMPA receptor severely affecting synaptic transmission. Anti-GluA2 antibodies induce receptor internalization with the concomitant reduction of synaptic GluA2-containing AMPARs, which impairs synaptic plasticity and memory in animals treated with patient antibodies. This work also links the disease symptoms to a specific immune-neuronal rearrangement of AMPA receptor subunit.
This two works published in prestigious Neuroscience journals shed light on the molecular mechanisms underlying autoimmune encephalitis that affect synaptic proteins providing a framework to explain disease symptoms.
For more information:
“Human Autoantibodies against the AMPA Receptor Subunit GluA2 Induce Receptor Reorganization and Memory Dysfunction” (Neuron, 2018; Oct 10;100(1):91-105)
“LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory” (Brain, 2018; Nov 1;141(11):3144-3159)