Megalencephalic leukoencephalopathy with subcortical cysts protein-1 regulates epidermal growth factor receptor signaling in astrocytes

Angela Lanciotti, Maria Stefania Brignone, Sergio Visentin, Chiara De Nuccio, Luigi Catacuzzeno, Cinzia Mallozzi, Stefania Petrini, Martino Caramia, Caterina Veroni, Gaetana Minnone, Antonietta Bernardo, Fabio Franciolini, Mauro Pessia, Enrico Bertini, Tamara Corinna Petrucci, Elena Ambrosini

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)


Mutations in the MLC1 gene, which encodes a protein expressed in brain astrocytes, are the leading cause of MLC, a rare leukodystrophy characterized by macrocephaly, brain edema, subcortical cysts, myelin and astrocyte vacuolation. Although recent studies indicate that MLC1 protein is implicated in the regulation of cell volume changes, the exact role of MLC1 in brain physiology and in the pathogenesis of MLC disease remains to be clarified. In preliminary experiments, we observed that MLC1 was poorly expressed inhighly proliferating astrocytomacellswhencomparedwith primaryastrocytes, and thatmodulation ofMLC1 expression influenced astrocyte growth. Because volume changes are key events in cell proliferation and during brain development MLC1 expression is inversely correlated to astrocyte progenitor proliferation levels,we investigated the possible role for MLC1 in the control of astrocyte proliferation.We found that overexpression ofwild type but notmutantMLC1 in human astrocytomacells hampered cell growth by favoring epidermal growth factor receptor (EGFR) degradation and by inhibiting EGF-induced Ca+ entry, ERK1/2 and PLCγ1 activation, and calcium-activated KCa3.1 potassium channel function, all molecular pathways involved in astrocyte proliferation stimulation. Interestingly, MLC1 did not influence AKT, an EGFR-stimulated kinase involved in cell survival. Moreover, EGFR expressionwas higher inmacrophages derived fromMLC patients than fromhealthy individuals. Since reactive astrocytes proliferate and re-express EGFR in response to different pathological stimuli, the present findings provide new information on MLC pathogenesis and unravel an important role for MLC1 in other brain pathological conditions where astrocyte activation occurs.

Original languageEnglish
Article numberddw032
Pages (from-to)1543-1558
Number of pages16
JournalHuman Molecular Genetics
Issue number8
Publication statusPublished - Apr 15 2016
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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