Research Focus
Unravelling the role of Humanin

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Abstract

Humanin (HN), a recently identified neuroprotective factor against Alzheimer's disease-related insults, has been reported to function as an anti cell-death factor through multiple mechanisms. One mechanism, revealed in a glioblastoma cell line, involves the apoptosis-inducing protein Bax. This, in addition to the fact that HN is produced in certain normal tissues, such as testis, implies a potential role of HN in oncogenesis. A second mechanism, in neuronal cells, is via a putative cell-surface receptor. It is through this mechanism that HN exhibits its neuroprotective activity.

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

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Cited by (69)

  • SH3-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 Chemistry
    Citation 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.

Deceased October 17th, 2003.

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