Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors.
More than 30 mutations in LGI1, a secreted neuronal protein, have been reported with autosomal dominant lateral temporal lobe epilepsy (ADLTE). Although LGI1 haploinsufficiency is thought to cause ADLTE, the underlying molecular mechanism that results in abnormal brain excitability remains mysterious. Here, we focused on a mode of action of LGI1 autoantibodies associated with limbic encephalitis (LE), which is one of acquired epileptic disorders characterized by subacute onset of amnesia and seizures. We comprehensively screened human sera from patients with immune-mediated neurological disorders for LGI1 autoantibodies, which also uncovered novel autoantibodies against six cell surface antigens including DCC, DPP10, and ADAM23. Our developed ELISA arrays revealed a specific role for LGI1 antibodies in LE and concomitant involvement of multiple antibodies, including LGI1 antibodies in neuromyotonia, a peripheral nerve disorder. LGI1 antibodies associated with LE specifically inhibited the ligand-receptor interaction between LGI1 and ADAM22/23 by targeting the EPTP repeat domain of LGI1 and reversibly reduced synaptic AMPA receptor clusters in rat hippocampal neurons. Furthermore, we found that disruption of LGI1-ADAM22 interaction by soluble extracellular domain of ADAM22 was sufficient to reduce synaptic AMPA receptors in rat hippocampal neurons and that levels of AMPA receptor were greatly reduced in the hippocampal dentate gyrus in the epileptic LGI1 knock-out mouse. Therefore, either genetic or acquired loss of the LGI1-ADAM22 interaction reduces the AMPA receptor function, causing epileptic disorders. These results suggest that by finely regulating the synaptic AMPA receptors, the LGI1-ADAM22 interaction maintains physiological brain excitability throughout life.
Division of Membrane Physiology, Department of Cell Physiology, National Institute for Physiological Sciences (NIPS), Okazaki 444-8787, Japan; Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan; Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Science, Kagoshima 890-8544, Japan; and Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Chiyoda-ku, Tokyo 102-0075, Japan.
Toshika
T
Ohkawa
Yuko
Y
Fukata
Miwako
M
Yamasaki
Taisuke
T
Miyazaki
Norihiko
N
Yokoi
Hiroshi
H
Takashima
Masahiko
M
Watanabe
Osamu
O
Watanabe
Masaki
M
Fukata
D051722:ADAM Proteins / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D004827:Epilepsy / Q000097:blood* / Q000175:diagnosis; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D020363:Limbic Encephalitis / Q000097:blood* / Q000175:diagnosis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D055815:Young Adult
D001323:Autoantibodies; D047908:Intracellular Signaling Peptides and Proteins; C116499:LGI1 protein, human; D009419:Nerve Tissue Proteins; D011506:Proteins; D018091:Receptors, AMPA; D051722:ADAM Proteins; C498474:ADAM22 protein, human