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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.

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Acknowledgments

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 (http://www.imperial.ac.uk/medicine/multiple-sclerosis-and-parkinsons-tissue-bank) for providing brain tissue samples.

Funding

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.

Author information

Author notes

  1. Brignone Maria Stefania and Lanciotti Angela contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy

    Maria Stefania Brignone, Angela Lanciotti, Barbara Serafini, Cinzia Mallozzi, Marco Sbriccoli, Caterina Veroni, Tamara Corinna Petrucci & Elena Ambrosini

  2. Department of FARVA, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy

    Paola Molinari

  3. Unitat de Fisiologia, Departamento de Ciències Fisiològiques, IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L’Hospitalet de Llobregat, Spain

    Xabier Elorza-Vidal & Raul Estévez

  4. Centro de Investigación en Red de Enfermedades Raras (CIBERER), ISCIII, Valenciana, Spain

    Raul Estévez

Authors
  1. Maria Stefania Brignone
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  2. Angela Lanciotti
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  3. Barbara Serafini
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  4. Cinzia Mallozzi
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  5. Marco Sbriccoli
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  6. Caterina Veroni
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  7. Paola Molinari
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  8. Xabier Elorza-Vidal
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  9. Tamara Corinna Petrucci
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  10. Raul Estévez
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  11. Elena Ambrosini
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Corresponding author

Correspondence to Elena Ambrosini.

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Brignone, M.S., Lanciotti, A., Serafini, B. et al. Megalencephalic Leukoencephalopathy with Subcortical Cysts Protein-1 (MLC1) Counteracts Astrocyte Activation in Response to Inflammatory Signals. Mol Neurobiol 56, 8237–8254 (2019). https://doi.org/10.1007/s12035-019-01657-y

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  • DOI: https://doi.org/10.1007/s12035-019-01657-y

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