Peptides modeled after the alpha-domain of metallothionein induce neurite outgrowth and promote survival of cerebellar granule neurons.
Metallothionein (MT) is a metal-binding protein capable of preventing oxidative stress and apoptotic cell death in the central nervous system of mammals, and hence is of putative therapeutic value in the treatment of neurodegenerative disorders. Recently, we demonstrated that a peptide modeled after the beta-domain of MT, EmtinB, induced neurite outgrowth and increased neuronal survival through binding to receptors of the low-density lipoprotein receptor family (LDLR). The present study identified two MT alpha-domain-derived peptide sequences termed EmtinAn and EmtinAc, each consisting of 14 amino acids, as potent stimulators of neuronal differentiation and survival of primary neurons. In addition, we show that a peptide derived from the N-terminus of the MT beta-domain, EmtinBn, promotes neuronal survival. The neuritogenic and survival promoting effects of EmtinAc, similar to MT and EmtinB but not EmtinAn, were dependent on the functional integrity of LDLR. Moreover, EmtinAn and EmtinAc induced activation of extracellular signal-regulated kinase (ERK) and protein kinase B (PKB/Akt). We suggest that multiple functional sites of MT serve to cross-link MT receptor(s), thereby transducing signals leading to an increase in neurite outgrowth and survival.
Asmussen
Johanne Wirenfeldt
JW
Protein Laboratory, Institute of Neuroscience and Pharmacology, University of Copenhagen, Panum Institute 24.2, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. johannene@sund.ku.dk
Ambjørn
Malene
M
Bock
Elisabeth
E
Berezin
Vladimir
V
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008668:Metallothionein / Q000737:chemistry*; D008969:Molecular Sequence Data; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018110:Receptors, Lipoprotein / Q000378:metabolism
D010455:Peptides; D018110:Receptors, Lipoprotein; D008668:Metallothionein; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases