OPALIN is an LGI1 receptor promoting oligodendrocyte differentiation.

in Proceedings of the National Academy of Sciences of the United States of America by Xiao-Yu Teng, Ping Hu, Cai-Ming Zhang, Qin-Xin Zhang, Guolin Yang, Yan-Yu Zang, Zhi-Xiong Liu, Guiquan Chen, Yun Stone Shi

TLDR

  • The study investigates how a protein called LGI1 helps myelination in the brain. The researchers found that LGI1 binds to a protein called OPALIN on the surface of cells called oligodendrocytes. When OPALIN is removed from these cells, myelination is impaired, and white matter abnormalities occur. The researchers also found that re-expressing OPALIN can restore myelination. This study provides important insights into the role of LGI1 and OPALIN in myelination and could lead to new treatments for LGI1-related disorders.

Abstract

Leucine-rich glioma-inactivated protein 1 (LGI1), a secretory protein in the brain, plays a critical role in myelination; dysfunction of this protein leads to hypomyelination and white matter abnormalities (WMAs). Here, we hypothesized that LGI1 may regulate myelination through binding to an unidentified receptor on the membrane of oligodendrocytes (OLs). To search for this hypothetic receptor, we analyzed LGI1 binding proteins through LGI1-3 × FLAG affinity chromatography with mouse brain lysates followed by mass spectrometry. An OL-specific membrane protein, the oligodendrocytic myelin paranodal and inner loop protein (OPALIN), was identified. Conditional knockout (cKO) of OPALIN in the OL lineage caused hypomyelination and WMAs, phenocopying LGI1 deficiency in mice. Biochemical analysis revealed the downregulation of Sox10 and Olig2, transcription factors critical for OL differentiation, further confirming the impaired OL maturation incKO mice. Moreover, virus-mediated re-expression of OPALIN successfully restored myelination incKO mice. In contrast, re-expression of LGI1-unbound OPALIN_K23A/D26A failed to reverse the hypomyelination phenotype. In conclusion, our study demonstrated that OPALIN on the OL membrane serves as an LGI1 receptor, highlighting the importance of the LGI1/OPALIN complex in orchestrating OL differentiation and myelination.

Overview

  • The study investigates the role of LGI1 in myelination and its potential receptor on the OL membrane. The hypothesis is that LGI1 regulates myelination through binding to an unidentified receptor on the OL membrane. The methodology involves LGI1-3 × FLAG affinity chromatography with mouse brain lysates followed by mass spectrometry to identify LGI1 binding proteins. OPALIN, an OL-specific membrane protein, is identified as the LGI1 receptor. The study aims to understand the mechanism of LGI1-mediated myelination and identify potential therapeutic targets for LGI1-related disorders.

Comparative Analysis & Findings

  • The study identifies OPALIN as the LGI1 receptor on the OL membrane. Conditional knockout (cKO) of OPALIN in the OL lineage causes hypomyelination and white matter abnormalities (WMAs), phenocopying LGI1 deficiency in mice. Biochemical analysis reveals the downregulation of Sox10 and Olig2, transcription factors critical for OL differentiation, further confirming the impaired OL maturation in cKO mice. Re-expression of OPALIN successfully restores myelination in cKO mice, while re-expression of LGI1-unbound OPALIN_K23A/D26A fails to reverse the hypomyelination phenotype. These findings suggest that the LGI1/OPALIN complex plays a critical role in orchestrating OL differentiation and myelination.

Implications and Future Directions

  • The study highlights the importance of the LGI1/OPALIN complex in myelination and identifies potential therapeutic targets for LGI1-related disorders. Future research should focus on understanding the molecular mechanisms underlying the LGI1/OPALIN complex and its role in myelination. Additionally, further studies are needed to investigate the potential therapeutic benefits of targeting the LGI1/OPALIN complex in LGI1-related disorders.
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