14-3-3 proteins stabilize LGI1-ADAM22 levels to regulate seizure thresholds in mice

Cell Rep. 2021 Dec 14;37(11):110107. doi: 10.1016/j.celrep.2021.110107.

Abstract

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 ∼50% of LGI1 and ∼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.

Keywords: 14-3-3; ADAM22; LGI1; PKA; epilepsy; mouse models; phosphorylation; precision medicine; seizure threshold; synapse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / genetics
  • 14-3-3 Proteins / metabolism*
  • ADAM Proteins / physiology*
  • Animals
  • Brain / metabolism*
  • Brain / pathology
  • Epilepsy / metabolism
  • Epilepsy / pathology
  • Epilepsy / prevention & control*
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation*
  • Nerve Tissue Proteins / physiology*

Substances

  • 14-3-3 Proteins
  • Intracellular Signaling Peptides and Proteins
  • Lgi1 protein, mouse
  • Nerve Tissue Proteins
  • ADAM Proteins
  • Adam22 protein, mouse