First Author | Yokoi N | Year | 2021 |
Journal | Cell Rep | Volume | 37 |
Issue | 11 | Pages | 110107 |
PubMed ID | 34910912 | Mgi Jnum | J:328338 |
Mgi Id | MGI:6881875 | Doi | 10.1016/j.celrep.2021.110107 |
Citation | Yokoi N, et al. (2021) 14-3-3 proteins stabilize LGI1-ADAM22 levels to regulate seizure thresholds in mice. Cell Rep 37(11):110107 |
abstractText | What percentage of the protein function is required to prevent disease symptoms is a fundamental question in genetic disorders. Decreased transsynaptic LGI1-ADAM22 protein complexes, because of their mutations or autoantibodies, cause epilepsy and amnesia. However, it remains unclear how LGI1-ADAM22 levels are regulated and how much LGI1-ADAM22 function is required. Here, by genetic and structural analysis, we demonstrate that quantitative dual phosphorylation of ADAM22 by protein kinase A (PKA) mediates high-affinity binding of ADAM22 to dimerized 14-3-3. This interaction protects LGI1-ADAM22 from endocytosis-dependent degradation. Accordingly, forskolin-induced PKA activation increases ADAM22 levels. Leveraging a series of ADAM22 and LGI1 hypomorphic mice, we find that approximately 50% of LGI1 and approximately 10% of ADAM22 levels are sufficient to prevent lethal epilepsy. Furthermore, ADAM22 function is required in excitatory and inhibitory neurons. These results suggest strategies to increase LGI1-ADAM22 complexes over the required levels by targeting PKA or 14-3-3 for epilepsy treatment. |