Søren Kragh Moestrup

Metallothionein and a peptide modeled after metallothionein, EmtinB, induce neuronal differentiation and survival through binding to receptors of the low-density lipoprotein receptor family.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Malene Ambjørn, Denmark
  • Johanne W Asmussen, Denmark
  • Mats Lindstam, Denmark
  • Kamil Gotfryd, Denmark
  • Christian Jacobsen, Denmark
  • Vladislav V Kiselyov, Denmark
  • Søren K Moestrup
  • Milena Penkowa, Denmark
  • Elisabeth Bock, Denmark
  • Vladimir Berezin, Denmark
  • Department of Medical Biochemistry
Accumulating evidence suggests that metallothionein (MT)-I and -II promote neuronal survival and regeneration in vivo. The present study investigated the molecular mechanisms underlying the differentiation and survival-promoting effects of MT and a peptide modeled after MT, EmtinB. Both MT and EmtinB directly stimulated neurite outgrowth and promoted survival in vitro using primary cultures of cerebellar granule neurons. In addition, expression and surface localization of megalin, a known MT receptor, and the related lipoprotein receptor-related protein-1 (LRP) are demonstrated in cerebellar granule neurons. By means of surface plasmon resonance MT and EmtinB were found to bind to both megalin and LRP. The bindings were abrogated in the presence of receptor-associated protein-1, an antagonist of the low-density lipoprotein receptor family, which also inhibited MT- and EmtinB-induced neurite outgrowth and survival. MT-mediated neurite outgrowth was furthermore inhibited by an anti-megalin serum. EmtinB-mediated inhibition of apoptosis occurred without a reduction of caspase-3 activity, but was associated with reduced expression of the pro-apoptotic B-cell leukemia/lymphoma-2 interacting member of cell death (Bim(S)). Finally, evidence is provided that MT and EmtinB activate extracellular signal-regulated kinase, protein kinase B, and cAMP response element binding protein. Altogether, these results strongly suggest that MT and EmtinB induce their neuronal effects through direct binding to surface receptors belonging to the low-density lipoprotein receptor family, such as megalin and LRP, thereby activating signal transduction pathways resulting in neurite outgrowth and survival.
Udgivelsesdato: 2008-Jan
Original languageEnglish
JournalJournal of Neurochemistry
Volume104
Issue1
Pages (from-to)21-37
Number of pages16
ISSN0022-3042
DOIs
Publication statusPublished - 2007

    Research areas

  • Analysis of Variance, Animals, Animals, Newborn, Cell Differentiation, Cell Survival, Cells, Cultured, Cerebellum, Dose-Response Relationship, Drug, In Situ Nick-End Labeling, LDL-Receptor Related Protein 2, LDL-Receptor Related Protein-Associated Protein, Metallothionein, Models, Biological, Neurites, Neurons, Peptides, Protein Binding, Rats, Rats, Wistar, Receptors, LDL, Signal Transduction, Surface Plasmon Resonance

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