Abstract
Anti-IgLON5 disease is a progressive neurological disorder associated with autoantibodies against a neuronal cell adhesion molecule, IgLON5. In human postmortem brain tissue, the neurodegeneration and accumulation of hyperphosphorylated tau (p-tau) are found. Whether IgLON5 antibodies induce neurodegeneration or neurodegeneration provokes an immune response causing inflammation and antibody formation remains to be elucidated. We investigated the effects of anti-IgLON5 antibodies on human neurons. Human neural stem cells were differentiated for 14–48 days and exposed from Days 9 to 14 (short-term) or Days 13 to 48 (long-term) to either (i) IgG from a patient with confirmed anti-IgLON5 antibodies or (ii) IgG from healthy controls. The electrical activity of neurons was quantified using multielectrode array assays. Cultures were immunostained for β-tubulin III and p-tau and counterstained with 4′,6-Diamidine-2′-phenylindole dihydrochloride (DAPI). To study the impact on synapses, cultures were also immunostained for the synaptic proteins postsynaptic density protein 95 (PSD95) and synaptophysin. A lactate dehydrogenase release assay and nuclei morphology analysis were used to assess cell viability. Cultures exposed to anti-IgLON5 antibodies showed reduced neuronal spike rate and synaptic protein content, and the proportion of neurons with degenerative appearance including p-tau (T205)-positive neurons was higher when compared to cultures exposed to control IgG. In addition, cell death was increased in cultures exposed to anti-IgLON5 IgG for 21 days. In conclusion, pathological anti-IgLON5 antibodies induce neurodegenerative changes and cell death in human neurons. This supports the hypothesis that autoantibodies may induce the neurodegenerative changes found in patients with anti-IgLON5-mediated disease. Furthermore, this study highlights the potential use of stem cell-based in vitro models for investigations of antibody-mediated diseases. As anti-IgLON5 disease is heterogeneous, more studies with different IgLON5 antibody samples tested on human neurons are needed.
Highlights
This article is an open access articleAnti-IgLON5 disease is a novel neurological disorder, thought to be autoantibody mediated, but with a distinct neurodegenerative pattern on postmortem tissue [1,2]
Similar to human neural stem cells (hNSC)-derived cultures exposed to anti-IgLON5 IgG, we found no difference in cell death for human-induced pluripotent stem cells (hiPSCs)-derived cultures after 7 days of exposure
Similar to the hNSC cultures, we found that anti-IgLON5 IgG reduced the amount of cell surface IgLON5 clusters in hiPSC cultures
Summary
Anti-IgLON5 disease is a novel neurological disorder, thought to be autoantibody mediated, but with a distinct neurodegenerative pattern on postmortem tissue [1,2] It was initially recognized as a sleep disorder with nonrapid eye movement (NREM) and REM parasomnia, breathing dysfunction, gait instability, and bulbar symptoms, but it is known to be more clinically heterogeneous in its presenting symptomatology and response distributed under the terms and conditions of the Creative Commons. Postmortem analyses have revealed neuronal deposits of hyperphosphorylated tau (p-tau) protein in the hypothalamus and the brainstem tegmentum [2] This deposition, consisting of three and four repeat isoforms, has a different distribution compared to other neurodegenerative conditions, suggesting anti-IgLON5 disease to be a novel tauopathy [1,6,7]. The clinical manifestations of the disease were initially divided into four main phenotypes: (1) predominant sleep disorder,
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