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Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, Kita Y, Kawasumi M, Kouyama K, Doyu M, Sobue G, Koide T, Tsuji S, Lang J, Kurokawa K, Nishimoto I. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6336-41. PubMed.
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There are some unusual things in this paper. They have a mRNA that is almost 1600 bases long, with an open reading frame of 75 bases, coding for a protein (peptide really) of 24 amino acids. Very unusual. When I run the sequence in Blast, it seems to be from a mitochrondrial DNA sequence. However, this is not mentioned in the paper. The implication is that a mitochrondrial gene giving rise to a 24 amino acid peptide, which seems to function extracellularly, at least in it's protective actions. This requires further explanation. Also, whether this peptide really exists in the brain is unclear: there is no blot to show whether it does or not. The protective actions are in cell culture systems of questionable relevance to AD. None of these systems can readily be extended to the mouse brain, let alone the human.
To whom it may concern,
I sent my comment, as one of the authors, when Dr. Davies' comment appeared here about a year ago. I am writing my updated comment in order to respond to Dr. Davies' comment since more facts about Humanin were found from us as well as from other groups.
First, to the comment of one of unusual things that we have mRNA that is almost 1600 bases long, with an open reading frame of 75 bases, coding for a peptide of 24 amino acids: Even though the long 1567-base HN cDNA has unusual structure where it encodes the short HN-ORF of 75 base, the long cDNA are 99% identical to certain registered human mRNA and when the long cDNA was transfected in mammalian cells, the transcription activity was able to lead the production of HN peptide despite the unusual structure. Although HN peptide has no signal peptide sequence at the N-terminus, it has been clarified that secretory activity is encoded by the full-length HN itself.
Second, to the comment of another unusual thing that HN cDNA seems to be mitochondrial DNA:.The entire region of HN cDNA is identical to both mitochondrial DNA corresponding to 16S rRNA and nuclear mRNA registered. One possibility is that HN peptide is an artificial protein encoded by a non-functional ORF in 16S rRNA. All mitochondrial rRNA transiently attached a polyA tail during transcription and the 16SrRNA was polyadenylated for the transcription. Another possibility is that the source of HN cDNA is nuclear and the HN peptide is produced from HN mRNA. Indeed, long HN cDNA containing HN ORF are identical to registered mRNA.
In order to clarify these possibilities, we examined whether HN express in vivo by anti-HN antibody. Immunoblot analysis detected a 3kDa protein with HN immunoreactivity, whose immunoreactivity is absorbed by synthetic HN, in the testis and the cloln in 3-week-old mice. HN immunoreactivity was also detected in an AD brain (see below). This publication (Tajima H. et al, 2002) showed that HN peptide is produced in vivo. Therefore, HN cDNA origin is nuclear. At the same time, there becomes no evidence that HN cDNA is likely mitochondrial 16S rRNA with a poly(A) tail.
Recently, rat homologue of Humanin, termed Rattin, was identified from another group in Italy (Caricasole et al., 2002) and Rattin's similar functions to HN were confirmed.
Third, to the question whether HN peptide really exists in the brain: We examined HN immunoreactivity in AD brain by anti-HN antibody (Tajima et al., 2002). In an AD brain, HN immunoreactivity was detected in some of the intact large neurons in the occipital lobes while no similar immunostaining was detected in neurons in an age-matched control brain. We also detected HN immunostaining in small round reactive glias in hippocampus while age matched control brain exhibited only few HN immunoreactive glias.
References:
Tajima H, Niikura T, Hashimoto Y, Ito Y, Kita Y, Terashita K, Yamazaki K, Koto A, Aiso S, Nishimoto I. Evidence for in vivo production of Humanin peptide, a neuroprotective factor against Alzheimer's disease-related insults. Neurosci Lett. 2002 May 24;324(3):227-31. PubMed.
Caricasole A, Bruno V, Cappuccio I, Melchiorri D, Copani A, Nicoletti F. A novel rat gene encoding a Humanin-like peptide endowed with broad neuroprotective activity. FASEB J. 2002 Aug;16(10):1331-3. PubMed.
Tajima H, Niikura T, Hashimoto Y, Ito Y, Kita Y, Terashita K, Yamazaki K, Koto A, Aiso S, Nishimoto I. Evidence for in vivo production of Humanin peptide, a neuroprotective factor against Alzheimer's disease-related insults. Neurosci Lett. 2002 May 24;324(3):227-31. PubMed.
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