A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Aβ

Abstract

There is no proof that the HN cDNA represents a gene, that its origin is nuclear, or that the HN peptide is produced in vivo. The information that the long HN cDNA sequence is virtually identical to mitochondrial rRNA should have been put in the Discussion rather than published as supplementary material. The Discussion should have contained the following:The long cDNA [1,567 bp including a poly(A) tail] containing the HN ORF is Ͼ99% identical (1548͞1552) to positions 1679-3230 of mitochondrial DNA (GenBank accession no. AB055387). Because mitochondrial DNA positions 1667-3224 code for mitochondrial 16S rRNA, and mitochondrial 16S rRNA has a short poly(A) tail during transcription (1), the virtual identity of the long HN cDNA to mitochondrial DNA indicates that HN cDNA is mitochondrial 16S rRNA with a poly(A) tail. This makes it unlikely that the peptide encoded by the ORF in HN cDNA is naturally produced. Further, the 75-bp HN ORF is separated from the 5Ј end of the long HN cDNA by a 950-bp region containing at least seven ORFs, each with a stop codon. This makes it even more unlikely that HN peptide is produced from the long HN cDNA. It should also be noted that mitochondria-like nuclear sequences occur commonly as pseudogenes (2). Finally, the HN peptide lacks the characteristic N-terminal signal sequence of secreted peptides, although we suggest that a signal peptide-like function may be encoded in the primary sequence of HN peptide. For all of these reasons, it is unlikely that the HN ORF leads to production of the predicted peptide in vivo.Nonetheless, it remains possible that HN cDNA represents a nuclear transcribed mRNA and that the HN peptide is a natural product. Long regions of the HN cDNA are Ͼ99% identical to certain registered human mRNAs [1545͞1553 at positions 14-1580 of FLJ22981 fis cDNA (AK026634), 925͞929 at positions 1-929 of FLJ22517 fis cDNA, 914͞919 at positions 1348-2266 of FLJ20341 fis cDNA, and 345͞346 at positions 1-346 of PNAS-32 mRNA]. PNAS-32 mRNA is actually expressed to produce NB4 apoptosis-related protein, showing that this mRNA is transcribed from a nuclear gene. In addition, HN cDNA is highly similar to regions of more than 1,000 bp on human chromosomes [positions 245364-244075 of chromosome 11 draft sequence (92%, 1198͞1290), positions 65752-66775 of chromosome X draft sequence (95%, 974͞1025), and positions 687598-688608 of chromosome 5 draft sequence (93%, 954͞1016)]. Also, the HN ORF has a Kozak-like sequence, although it is not canonical.

The mitochondrial‐derived peptide MOTS‐c: a player in exceptional longevity?

“…These include humanin , a 24‐amino acid peptide encoded in the 16S rRNA region with strong cytoprotective actions (Hashimoto et al ., 2001) and the recently discovered mitochondrial open reading frame of the 12S rRNA‐c (MOTS‐c), which is a 16‐amino acid peptide that regulates insulin sensitivity and metabolic homeostasis (Lee et al ., 2015). We have recently suggested that MOTS‐c might also be involved in the aging process (Alis et al ., 2015).…”

Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities

“…91 HN was originally identified as an anti-apoptotic peptide encoded in a cDNA that rescued neuronal cells from apoptosis induced by presenilin mutants associated with familial Alzheimer's disease and by amyloid-beta-protein, during a functional screen of a cDNA library prepared from the brain of an autopsy-confirmed Alzheimer's disease patient. 92 93,94 In this regard, though the 3D structure of Bim-EL is presently unknown, the structures of Bax and Bid are similar, implying that the HN peptide may recognize a conserved structural feature of these proteins. Understanding of the mechanism by which HN suppresses Bax, Bid, and BimEL would be greatly enhanced by the solving of the 3D-structure of a complex of HN with at least one of these proapoptotic proteins.…”

Protective effects of tetramethylpyrazine on rat retinal cell cultures

“…In this regard, Bcl-2 family members are the central regulators for the mitochondrial membrane permeability (Kroemer and Reed, 2000). Among a long list of Bcl-2 interacting molecules, humanin as well as its homolog, i.e., rattin, is recently identified as a small antiapoptotic peptide in human and rodent cells, respectively (Hashimoto et al, 2001;Caricasole et al, 2002). Through interacting with Bid to inhibit Bax protein activity, humanin has been found to protect neuronal cells from a variety of toxic insults (Guo et al, 2003;Nishimoto et al, 2004).…”