Autoantibodies to synapsin I sequestrate synapsin I and alter synaptic function

• Published in: Cell death & disease Vol. 10; no. 11; p. 864
• Main Authors: Rocchi, Anna, Sacchetti, Silvio, De Fusco, Antonio, Giovedi, Silvia, Parisi, Barbara, Cesca, Fabrizia, Höltje, Markus, Ruprecht, Klemens, Ahnert-Hilger, Gudrun, Benfenati, Fabio
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.11.2019; Springer Nature B.V
• Subjects: 13/1; 14; 14/19; 14/28; 14/63; 631/378/1689/1666; 631/378/87; 631/80/304; 64/60; 692/699/249/1313; 82/83; 9/74; Animals; Antibodies; Antigens; Autoantibodies; Autoantibodies - genetics; Autoantibodies - immunology; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cytoplasm - genetics; Cytoplasm - immunology; Encephalitis; Endocytosis; GABAergic Neurons - immunology; GABAergic Neurons - metabolism; Glutamatergic transmission; Hippocampus; Humans; Immunology; Intracellular; Life Sciences; Limbic Encephalitis - genetics; Limbic Encephalitis - immunology; Mice; Mimicry; Nerve endings; Nervous System Diseases - genetics; Nervous System Diseases - immunology; Neurological diseases; Neurons; Phenotypes; Protein Transport - genetics; Synapses - genetics; Synapses - immunology; Synapsin I; Synapsins - genetics; Synapsins - immunology; Synaptic transmission; Synaptic Transmission - genetics; Synaptic Transmission - immunology; Synaptic vesicles; Synaptic Vesicles - genetics; Synaptic Vesicles - immunology; γ-Aminobutyric acid
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-2106-z

Synapsin I is a phosphoprotein that coats the cytoplasmic side of synaptic vesicles and regulates their trafficking within nerve terminals. Autoantibodies against Syn I have been described in sera and cerebrospinal fluids of patients with numerous neurological diseases, including limbic encephalitis and clinically isolated syndrome; however, the effects and fate of autoantibodies in neurons are still unexplored. We found that in vitro exposure of primary hippocampal neurons to patient’s autoantibodies to SynI decreased the density of excitatory and inhibitory synapses and impaired both glutamatergic and GABAergic synaptic transmission. These effects were reproduced with a purified SynI antibody and completely absent in SynI knockout neurons. Autoantibodies to SynI are internalized by FcγII/III-mediated endocytosis, interact with endogenous SynI, and promote its sequestration and intracellular aggregation. Neurons exposed to human autoantibodies to SynI display a reduced density of SVs, mimicking the SynI loss-of-function phenotype. Our data indicate that autoantibodies to intracellular antigens such as SynI can reach and inactivate their targets and suggest that an antibody-mediated synaptic dysfunction may contribute to the evolution and progression of autoimmune-mediated neurological diseases positive for SynI autoantibodies.