Animal model for chronic fatigue syndrome: Model evaluation and establishment

摘要

RNA-binding proteins and axon guid- anceeurite outgrowth proteins have been repeatedly associated with the disease, although a direct pathogenic role of autoantibod- ies directed against intracellular antigens is still poorly understood. We recently described a case of limbic encephalitis associated with serum and CSF immunoglobulin IgA/IgG autoantibodies to the intracellular synaptic vesicle (SV)-associated protein synapsin I (SynI) that coats the cytoplasmic surface of SVs and regulates their trafficking within nerve terminals. We found that in vitro exposure of primary hippocampal neurons to patient’s autoanti- bodies to SynI decreased the density of excitatory and inhibitory synapses and impaired both glutamatergic and GABAergic synap- tic transmission. These effects were reproduced with a purified Syn! antibody and completely absent in SynI knockout neurons. Autoan- tibodies to Synl are internalized by FcylI/IlI-mediated endocytosis, interact with endogenous Synl, and promote its sequestration and intracellular aggregation. Neurons exposed to autoantibod- ies to SynI display a reduced density of SVs, mimicking the Synl loss-of-function phenotype. Our data indicate that autoan- tibodies to intracellular antigens such as Synl can reach and inactivate their targets and suggest that an antibody-mediated synaptic dysfunction is responsible for the pathogenesis and pro- gression of limbic encephalitis as well as for the evolution of other autoimmune-mediated neurological diseases positive for Synl autoantibodies.