Complete sequence of a novel protein containing a femtomolar-activity- dependent neuroprotective peptide

Merav Bassan, Rachel Zamostiano, Ariane Davidson, Albert Pinhasov, Eliezer Giladi, Orly Perl, Haim Bassan, Cila Blat, Gretchen Gibney, Gordon Glazner, Douglas E. Brenneman, Illana Gozes*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The vulnerability of neurons and the irreversibility of loss make discoveries of neuroprotective compounds fundamentally important. Here, the complete coding sequence of a novel protein (828 amino acids, pl 5.99), derived from mouse neuroglial cells, is revealed. The sequence contained (1) a neuroprotective peptide, NAPVSIPQ, sharing structural and immunological homologies with the previously reported, activity-dependent neurotrophic factor; (2) a glutaredoxin active site; and (3) a zinc binding domain. Gene expression was enriched in the mouse hippocampus and cerebellum and augmented in the presence of the neuropeptide vasoactive intestinal peptide, in cerebral cortical astrocytes. In mixed neuron-astrocyte cultures, NAPVSIPQ provided neuroprotection at subfemtomolar concentrations against toxicity associated with tetrodotoxin (electrical blockade), the β-amyloid peptide (the Alzheimer's disease neurotoxin), N-methyl-D-aspartate (excitotoxicity), and the human immunodeficiency virus envelope protein. Daily NAPVSIPQ injections to newborn apolipoprotein E-deficient mice accelerated the acquisition of developmental reflexes and prevented short-term memory deficits. Comparative studies suggested that NAPVSIPQ was more efficacious than other neuroprotective peptides in the apolipoprotein E-deficiency model. A potential basis for rational drug design against neurodegeneration is suggested with NAPVSIPQ as a lead compound. The relative enrichment of the novel mRNA transcripts in the brain and the increases found in the presence of vasoactive intestinal peptide, an established neuroprotective substance, imply a role for the cloned protein in neuronal function.

Original languageEnglish
Pages (from-to)1283-1293
Number of pages11
JournalJournal of Neurochemistry
Volume72
Issue number3
DOIs
StatePublished - 1999

Keywords

  • Apolipoprotein E
  • Learning and memory
  • Molecular cloning
  • Neuronal survival
  • Vasoactive intestinal peptide
  • mRNA

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