Megalencephalic Leukoencephalopathy with Subcortical Cysts Protein-1 (MLC1) Counteracts Astrocyte Activation in Response to Inflammatory Signals

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Abstract

Megalencephalic leukoencephalopathy with subcortical cysts protein-1 (MLC1) is a membrane protein expressed by perivascular astrocytes. MLC1 mutations cause MLC, an incurable leukodystrophy characterized by macrocephaly, brain edema, cysts, myelin vacuolation, and astrocytosis, leading to cognitive/motor impairment and epilepsy. Although its function is unknown, MLC1 favors regulatory volume decrease after astrocyte osmotic swelling and down-regulates intracellular signaling pathways controlling astrocyte activation and proliferation. By combining analysis of human brain tissues with in vitro experiments, here we investigated MLC1 role in astrocyte activation during neuroinflammation, a pathological condition exacerbating patient symptoms. MLC1 upregulation was observed in brain tissues from multiple sclerosis, Alzheimer's, and Creutzfeld-Jacob disease, all pathologies characterized by strong astrocytosis and release of inflammatory cytokines, particularly IL-1β. Using astrocytoma lines overexpressing wild-type (WT) or mutated MLC1 and astrocytes from control and Mlc1 knock-out (KO) mice, we found that IL-1β stimulated WT-MLC1 plasma membrane expression in astrocytoma cells and control primary astrocytes. In astrocytoma, WT-MLC1 inhibited the activation of IL-1β-induced inflammatory signals (pERK, pNF-kB) that, conversely, were constitutively activated in mutant expressing cells or abnormally upregulated in KO astrocytes. WT-MLC1+ cells also expressed reduced levels of the astrogliosis marker pSTAT3. We then monitored MLC1 expression timing in a demyelinating/remyelinating murine cerebellar organotypic culture model where, after the demyelination and release of inflammatory cytokines, recovery processes occur, revealing MLC1 upregulation in these latter phases. Altogether, these findings suggest that by modulating specific pathways, MLC1 contributes to restore astrocyte homeostasis after inflammation, providing the opportunity to identify drug target molecules to slow down disease progression.

Original languageEnglish
Pages (from-to)8237-8254
Number of pages18
JournalMolecular Neurobiology
Volume56
Issue number12
DOIs
Publication statusPublished - Dec 2019

Keywords

  • Adult
  • Aged
  • Alzheimer Disease/pathology
  • Animals
  • Astrocytes/metabolism
  • Cell Membrane/metabolism
  • Demyelinating Diseases/pathology
  • Disease Models, Animal
  • ErbB Receptors/metabolism
  • Extracellular Signal-Regulated MAP Kinases/metabolism
  • Female
  • Humans
  • Inflammation/pathology
  • Interleukin-1beta/metabolism
  • Male
  • Membrane Proteins/deficiency
  • Mice, Knockout
  • Middle Aged
  • Models, Biological
  • Mutation/genetics
  • NF-kappa B/metabolism
  • Phosphorylation
  • Rats
  • Signal Transduction
  • Up-Regulation

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