Molecular Neurobiology

, Volume 56, Issue 12, pp 8237–8254 | Cite as

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

  • Maria Stefania Brignone
  • Angela Lanciotti
  • Barbara Serafini
  • Cinzia Mallozzi
  • Marco Sbriccoli
  • Caterina Veroni
  • Paola Molinari
  • Xabier Elorza-Vidal
  • Tamara Corinna Petrucci
  • Raul Estévez
  • Elena AmbrosiniEmail author


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.


Leukodystrophy Neuroinflammation Neurodegeneration IL-1β pERK Astrocytosis 



We thank Dr. Antonella Bernardo for providing rat astrocyte cultures, Dr. Barbara Rosicarelli for technical assistance in the immunohistochemical work, and the UK Multiple Sclerosis Tissue Bank ( for providing brain tissue samples.


This work was supported by Italian Ministry of Health, Ricerca Finalizzata, (Grant N. GR-2013-02355882 to A.L.); European Leukodystrophies Association (ELA) (Grant N. ELA 2016-002F3 to M.S.B and ELA2012-014C2B to R.E.); TELETHON (Grant N. GEP14134 to E.A.); Spanish Ministerio de Ciencia e Innovación (MICINN) (SAF2015–70377 to R.E.); and the Generalitat de Catalunya (SGR2014–1178 to R.E.), (ERARE to R.E.). R.E. is a recipient of an ICREA Academia prize.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2019_1657_MOESM1_ESM.pdf (282 kb)
ESM 1 (PDF 281 kb)
12035_2019_1657_MOESM2_ESM.pdf (547 kb)
ESM 2 (PDF 547 kb)


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Authors and Affiliations

  • Maria Stefania Brignone
    • 1
  • Angela Lanciotti
    • 1
  • Barbara Serafini
    • 1
  • Cinzia Mallozzi
    • 1
  • Marco Sbriccoli
    • 1
  • Caterina Veroni
    • 1
  • Paola Molinari
    • 2
  • Xabier Elorza-Vidal
    • 3
  • Tamara Corinna Petrucci
    • 1
  • Raul Estévez
    • 3
    • 4
  • Elena Ambrosini
    • 1
    Email author
  1. 1.Department of NeuroscienceIstituto Superiore di SanitàRomeItaly
  2. 2.Department of FARVAIstituto Superiore di SanitàRomeItaly
  3. 3.Unitat de Fisiologia, Departamento de Ciències Fisiològiques, IDIBELL-Institute of NeurosciencesUniversitat de BarcelonaL’Hospitalet de LlobregatSpain
  4. 4.Centro de Investigación en Red de Enfermedades Raras (CIBERER), ISCIIIValencianaSpain

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