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LGI1-associated epilepsy through altered ADAM23-dependent neuronal morphology.
- Source :
-
Molecular and cellular neurosciences [Mol Cell Neurosci] 2009 Dec; Vol. 42 (4), pp. 448-57. Date of Electronic Publication: 2009 Sep 29. - Publication Year :
- 2009
-
Abstract
- Most epilepsy genes encode ion channels, but the LGI1 gene responsible for autosomal dominant partial epilepsy with auditory features produces a secreted protein. LGI1 is suggested to regulate PSD-95 via ADAM22. However, no unbiased screen of LGI1 action has been conducted. Here, we searched for brain genes supporting high affinity LGI-1 binding. ADAM23 was the only LGI1 interactor identified. The related proteins, ADAM22 and ADAM11, but not ADAM12, bind LGI1. Neither ADAM23 nor ADAM11, nor some forms of ADAM22, contain PDZ-interacting sequences, suggesting PSD-95-independent mechanisms in ADPEAF. Because ADAMs modulate integrins, we examined LGI1 effect on neurite outgrowth. LGI1 increases outgrowth from wild-type but not ADAM23-/- neurons. Furthermore, CA1 pyramidal neurons of ADAM23-/- hippocampi have reduced dendritic arborization. ADAM23-/- mice exhibit spontaneous seizures, while ADAM23+/- mice have decreased seizure thresholds. Thus, LGI1 binding to ADAM23 is necessary to correctly pattern neuronal morphology and altered anatomical patterning contributes to ADPEAF.
- Subjects :
- ADAM Proteins genetics
Animals
Behavior, Animal physiology
Binding Sites
Brain anatomy & histology
Brain metabolism
COS Cells
Chlorocebus aethiops
Epilepsy genetics
Epilepsy physiopathology
Humans
Intracellular Signaling Peptides and Proteins
Mice
Mice, Knockout
Nerve Tissue Proteins genetics
Neurons metabolism
Phenotype
Protein Isoforms genetics
Protein Isoforms metabolism
Proteins genetics
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins metabolism
ADAM Proteins metabolism
Epilepsy metabolism
Nerve Tissue Proteins metabolism
Neurons cytology
Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1095-9327
- Volume :
- 42
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular and cellular neurosciences
- Publication Type :
- Academic Journal
- Accession number :
- 19796686
- Full Text :
- https://doi.org/10.1016/j.mcn.2009.09.008