Trends in Molecular Medicine
Research FocusUnravelling the role of Humanin☆
Section snippets
The discovery of Humanin and the structural requirement for its neuroprotective activity
HN was originally identified by screening a cDNA library of the occipital lobe of an AD patient [1]. The isolation of HN cDNA and the determination of a functional open reading frame have been reviewed previously [10]. The structure/function relationship for the neuroprotective function of HN peptide has been investigated using systems in which neuronal cell death induced by AD-relevant insults has been quantitatively assessed (using Trypan blue exclusion assay, WST-8 assay and Calcein assay)
Multiple cell-death mechanisms
To establish therapeutic strategies, as well as to clarify the mechanism of AD pathogenesis, the mechanism of HN action must be understood. Does HN act from outside or inside the cell? If HN is to exert neuroprotection against AD-relevant insults such as Aβ, it must be secreted from the cell 1, 12. The basis for this assertion are: (i) part of the HN peptide translated from HN cDNA is secreted [1]; (ii) this secretion is greatly increased by cytosolic calcium stimulation and, to a lesser
In vivo expression of Humanin
It is important to determine whether HN is produced in vivo and, if so, whether it is transcribed from genomic or mitochondrial DNA [18]. Examination with anti-HN antibody revealed that HN immunoreactivity is detected in some of the intact large neurons in the occipital lobe of an AD brain, but not in the neurons of other brain regions or in the neurons of an age-matched control brain (Figure 2) [18]. HN immunoreactivity is also observed in small round reactive glias in the AD brain, most
HNG, a potent derivative of HN
HNG (S14G-HN) is a derivative of HN. Initially constructed as a negative control, the neuroprotective function of HNG (in neurohybrid cells against the product of FAD genes and in primary neurons against Aβ peptides) was 1000 times greater than that of HN [1]. The potentiation of HN neuroprotective function by Gly substitution for Ser14 is specifically mimicked by D-Ser isomerization [13]. Therefore, it is conceivable that the HN peptide is converted to the maximally active form by
Concluding remarks
HN was originally identified as a neuroprotective factor against AD-related neuronal cell death in a process requiring secretion, dimerization and the binding to an as yet unidentified receptor. Considering its broad range of activities against AD-relevant insults, HN offers a promising therapy for the suppression of neuronal loss in AD. A second anti-apoptotic mechanism for HN, interference with Bax, has recently been reported. Considering that deficiency in apoptosis frequently results in
References (21)
Multiple mechanisms underlie neurotoxicity by different type Alzheimer's disease mutations of amyloid precursor protein
J. Biol. Chem.
(2000)Identification of essential amino acids in Humanin, a neuroprotective factor against Alzheimer's disease relevant insults
Peptides
(2003)- et al.
Life-or-death decisions by the Bcl-2 protein family
Trends Biochem. Sci.
(2001) Evidence for in vivo production of Humanin peptide, a neuroprotective factor against Alzheimer's disease-related insults
Neurosci. Lett.
(2002)A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Aβ
Proc. Natl. Acad. Sci. U. S. A.
(2001)Apoptosis is induced by β-amyloid in cultured central nervous system neurons
Proc. Natl. Acad. Sci. U. S. A.
(1993)Neurotoxic mechanisms by Alzheimer's disease linked N141I mutant presenilin2
J. Pharmacol. Exp. Ther.
(2002)Neurotoxic mechanisms triggered by Alzheimer's disease-linked mutant M146L presenilin 1: involvement of NO synthase via a novel pertussis toxin target
J. Neurochem.
(2002)Humanin inhibits cell death of serum-deprived PC12h cells
Neuroreport
(2002)- et al.
Humanin rescues human cerebrovascular smooth muscle cells from Aβ-induced toxicity
J. Neurochem.
(2003)
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2018, Journal of Controlled ReleaseSH3-binding protein 5 mediates the neuroprotective effect of the secreted bioactive peptide humanin by inhibiting c-Jun NH<inf>2</inf>-terminal kinase
2013, Journal of Biological ChemistryCitation Excerpt :These results indicate that SH3BP5 is an inhibitor of JNK and plays a substantial role as a transcriptional target and a downstream effector of Humanin. Humanin and S14G-Humanin (named Humanin G and abbreviated HNG; a Humanin analog with a 1000-fold stronger activity) (1, 2) were synthesized by the Keck Foundation Biotechnology Resource Laboratory of Yale University. Recombinant rat IL-6 was purchased from R&D Systems (Minneapolis).
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This article was originally written by Ikuo Nishimoto (see Obituary following this article), and has been revised by Takako Niikura.
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Deceased October 17th, 2003.