Humanin antagonists: mutants that interfere with dimerization inhibit neuroprotection by Humanin.

Abstract

The 24-residue peptide Humanin (HN) protects neuronal cells from insults of various Alzheimer's disease (AD) genes and Abeta by forming a homodimer. We have previously shown that P3A, S7A, C8A, L9A, L12A, T13A, S14A and P19A mutations nullify the neuroprotective function of HN [Yamagishi, Y., Hashimoto, Y., Niikura, T. & Nishimoto, I. (2003) Peptides, 24, 585-595]. Here we examined whether any of these 'null' mutants could function as dominant-negative mutants. Homodimerization-defective mutants, P3A-, L12A-, S14A- and P19A-HN, specifically blocked neuroprotection by HN, but not by activity-dependent neurotrophic factor. Furthermore, insertion of S7A, the mutation that blocks the homodimerization of HN, but not insertion of G5A abolished the antagonizing function of L12A-HN. While L12A-HN and G5A/L12A-HN actually inhibited HN homodimerization, S7A/L12A-HN had no effect. These data indicate that P3A-, L12A-, S14A- and P19A-HN function as HN antagonists by forming an inactive dimer with HN. This study provides a novel insight into the understanding of the in vivo function of HN, as well as into the development of clinically applicable HN neutralizers.

• Authors: Yuichi Hashimoto, Kenzo Terashita, Takako Niikura, Yohichi Yamagishi, Miho Ishizaka, Kohsuke Kanekura, Tomohiro Chiba, Marina Yamada, Yoshiko Kita, Sadakazu Aiso, Masaaki Matsuoka, Ikuo Nishimoto
• Journal: The European journal of neuroscience (Eur J Neurosci) Vol. 19 Issue 9 Pg. 2356-64 (May 2004) ISSN: 0953-816X [Print] France
• PMID: 15128389 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Culture Media, Conditioned
• Intracellular Signaling Peptides and Proteins
• Nerve Tissue Proteins
• Neuropeptides
• Neuroprotective Agents
• Oligopeptides
• Peptide Fragments
• Peptides
• Proteins
• activity-dependent neurotrophic factor
• amyloid beta-protein (1-43)
• humanin

Topics

• Amyloid beta-Peptides (toxicity)
• Amyloid beta-Protein Precursor (adverse effects, genetics)
• Animals
• Blotting, Western (methods)
• Cell Count (methods)
• Cell Death (drug effects)
• Cell Survival (drug effects)
• Cerebral Cortex (cytology)
• Culture Media, Conditioned (pharmacology)
• Dimerization
• Dose-Response Relationship, Drug
• Drug Interactions
• Hybrid Cells
• Intracellular Signaling Peptides and Proteins
• Mice
• Mutation
• Nerve Tissue Proteins (pharmacology)
• Neuroblastoma
• Neurons
• Neuropeptides
• Neuroprotective Agents (pharmacology)
• Oligopeptides
• Peptide Fragments (toxicity)
• Peptides (pharmacology)
• Proteins (chemistry, genetics, pharmacology)
• Rats
• Transfection (methods)