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

The vulnerability of neurons and the irreversibility of loss make discoveri es of neuroprotective compounds fundamentally important. Here, the complete coding sequence of a novel protein (828 amino acids, pl 5.99), derived fro m mouse neuroglial cells, is revealed. The sequence contained (1) a neuropr otective 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 p resence of the neuropeptide vasoactive intestinal peptide, in cerebral cort ical astrocytes. In mixed neuron-astrocyte cultures, NAPVSIPQ provided neur oprotection at subfemtomolar concentrations against toxicity associated wit h tetrodotoxin (electrical blockade), the p-amyloid peptide (the Alzheimer' s disease neurotoxin), N-methyl-D-aspartate (excitotoxicity), and the human immunodeficiency virus envelope protein. Daily NAPVSIPQ injections to newb orn apolipoprotein E-deficient mice accelerated the acquisition of developm ental reflexes and prevented short-term memory deficits. Comparative studie s suggested that NAPVSIPQ was more efficacious than other neuroprotective p eptides in the apolipoprotein E-deficiency model. A potential basis for rat ional drug design against neurodegeneration is suggested with NAPVSIPQ as a lead compound. The relative enrichment of the novel mRNA transcripts in th e brain and the increases found in the presence of vasoactive intestinal pe ptide, an established neuroprotective substance, imply a role for the clone d protein in neuronal function.