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2024

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PNAS, Nanjing University Shi Yun/Chen Guiquan and other teams have jointly discovered a new mechanism for epilepsy-related proteins to regulate myelin development.

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Leucine-rich glioma-inactivating protein 1(LGI1) is a protein secreted in the brain and plays a key role in myelination; dysfunction of this protein results in hypomelination and white matter abnormalities (WMAs).

On July 31, 2024, Professor Shi Yun/Chen Guiquan from the Institute of Medical College of Nanjing University and the team of Hu Ping, a researcher at Nanjing Maternal and Child Health HospitalPNASpublished a report entitled"OPALIN is an LGI1 receptor promoting oligodendrocyte differentiation"The research paper,The study hypothesized that LGI1 may regulate myelination by binding to an unidentified receptor on the membrane of oligodendrocytes (OLs).To search for this hypothetical receptor, the authors analyzed the LGI1-binding protein by binding mouse brain lysates by LGI1-3 x FLAG affinity chromatography and performing mass spectrometry.Results One OL-specific membrane protein, oligodendrocyte myelin segment and loop protein (OPALIN), was identified.Conditional knockout (cKO)OPALIN in the OL lineage results in low myelination and WMAs, mimicking the LGI1 deficient phenotype.

Biochemical analysis revealed downregulation of Sox10 and Olig2, transcription factors that are critical for OL differentiation, further confirming impaired OL maturation in Opalin cKO mice. In addition, virus-mediated OPALIN re-expression successfully restored myelination in Opalin cKO mice. In contrast, re-expression of OPALIN_K23A/D26A, which failed to bind to LGI1, failed to reverse the low myelination phenotype.In conclusion, the authors' study shows that OPALIN on the OL membrane acts as a LGI1 receptor, highlighting the importance of the LGI1/OPALIN complex in coordinating OL differentiation and myelination.

White matter abnormalities (WMAs) can lead to long-term functional impairment, including cognitive decline, motor deficits, and dementia.In the brain, the main component of white matter is myelin, which is produced by mature oligodendrocytes (OLs), which are derived from oligodendrocyte precursor cells (OPCs). Oligodendrogliogenesis and myelination are highly regulated processes involving multiple mechanisms, including endogenous and exogenous mechanisms. Endogenous mechanisms require transcription factors to regulate oligodendrocyte differentiation and myelination, which function at the transcriptional, post-transcriptional, or epigenetic level, while exogenous mechanisms involve axonal surface ligands, secretory molecules, and axonal activity.Exogenous signals usually act through receptors expressed on the cell membrane of oligodendrocytes, ultimately regulating the intrinsic pathway.

LGI1 directly binds to OPALIN

Leucine-rich glioma inhibitor protein 1(LGI1) is a 64 kDa protein secreted primarily by neurons.Mutations in the LGI1 gene cause human autosomal dominant lateral temporal lobe epilepsy. Autoantibodies against LGI1 cause limbic encephalitis. In 2010, Silva et al. first reported that homozygous inactivation of LGI1 resulted in myelin reduction in mice. The authors recently found that Lgi1D51G/D51G mice carrying loss-of-function LGI1 mutants exhibit WMAs. Mechanistic studies suggest that LGI1 may promote oligodendrocyte differentiation and myelination through TSC-mTOR and Sox10-dependent endogenous signals.
Secreted proteins exert their function by binding to membrane receptors.Indeed, LGI1 regulates AMPAR receptor trafficking and localization of potassium channels by binding to neuronal receptors ADAM22 and ADAM23. In addition, LGI1 regulates axonal growth by interacting with axonal NgR1. However, to date, no receptor for LGI1 on oligodendrocytes has been reported. This prompted the authors to hypothesize that there is an as-yet undiscovered receptor on oligodendrocytes that mediates LGI1-regulated myelination. Through proteomic analysis, the authors identified oligodendrocyte-permyelinating nodule and inner ring protein (OPALIN, also known as TMEM10) as an interacting protein of LGI1.
OPALIN is a type I transmembrane protein expressed on oligodendrocytes.Co-immunoprecipitation experiments confirmed that OPALIN interacts with LGI1 through its extracellular domain and that Lys23 and Asp26 residues of OPALIN are essential for this interaction. Deletion of OPALIN in the oligodendrocyte lineage results in decreased WMAs and myelination. Mechanically, OPALIN deletion impairs oligodendrocyte differentiation by downregulating Sox10 and Olig2. In addition, adeno-associated virus (AAV)-dependent OPALIN overexpression, but not OPALIN_K23A/D26A, was effective in rescuing myelination in OPALIN-deficient mice. Thus, the authors' findings highlight the critical role of the LGI1/OPALIN complex in oligodendrocyte differentiation and myelination.

Teng Xiaoyu, a doctoral graduate of the Institute of models (now a postdoctoral fellow of Guangdong Institute of Intelligent Science and Technology), is the only first author of this paper. The research was supported by major projects of the Ministry of Science and Technology, the National Natural Science Foundation of China, the Central University Research Fund and the China Postdoctoral Science Foundation.

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