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Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts
Tania López-Hernández1, Sònia Sirisi, Xavier Capdevila-Nortes
1Sección de Fisiología, Idibell-Hospital Universitari de Bellvitge, Hospitalet de LLobregat, Universitat de Barcelona, Barcelona, Spain.
Abstract:
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy caused by mutations in MLC1 or GLIALCAM. The GLIALCAM gene product functions as an MLC1 beta-subunit. We aim to further clarify the molecular mechanisms of MLC caused by mutations in MLC1 or GLIALCAM. For this purpose, we analyzed a human post-mortem brain obtained from an MLC patient, who was homozygous for a missense mutation (S69L) in MLC1. We showed that this mutation affects the stability of MLC1 in vitro and reduces MLC1 protein levels in the brain to almost undetectable. However, the amount of GlialCAM and its localization were nearly unaffected, indicating that MLC1 is not necessary for GlialCAM expression or targeting. These findings were supported by experiments in primary astrocytes and in heterologous cells. In addition, we demonstrated that MLC1 and GlialCAM form homo- and hetero-complexes and that MLC-causing mutations in GLIALCAM mainly reduce the formation of GlialCAM homo-complexes, leading to a defect in the trafficking of GlialCAM alone to cell junctions. GLIALCAM mutations also affect the trafficking of its associated molecule MLC1, explaining why GLIALCAM and MLC1 mutations lead to the same disease: MLC.
Insights
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) results from mutations in MLC1 or GLIALCAM. This study reveals how these mutations disrupt protein complex formation and trafficking, leading to the disease.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic leukodystrophy.
- Mutations in MLC1 and GLIALCAM genes are known causes of MLC.
- GLIALCAM acts as a beta-subunit for the MLC1 protein.
Observation:
- Analyzed a post-mortem brain from an MLC patient with an MLC1 S69L mutation.
- Investigated the impact of MLC1 and GLIALCAM mutations on protein stability, expression, and localization in vitro and in cell models.
- Examined the formation of MLC1 and GlialCAM homo- and hetero-complexes.
Findings:
- An MLC1 mutation (S69L) severely reduced MLC1 protein levels but did not affect GlialCAM levels or localization.
- MLC1 is not essential for GlialCAM expression or targeting to cellular locations.
- GLIALCAM mutations primarily impair GlialCAM homo-complex formation, disrupting its trafficking to cell junctions.
- Mutations in GLIALCAM also negatively impact the trafficking of MLC1.
Implications:
- These findings clarify the molecular mechanisms underlying MLC caused by mutations in MLC1 and GLIALCAM.
- Understanding these protein interactions and trafficking defects provides insight into the pathogenesis of MLC.
- Identifies potential therapeutic targets for MLC by focusing on protein complex stability and cellular transport pathways.
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