An AD-related neuroprotector rescues transformed rat retinal ganglion cells from CoCl₂-induced apoptosis.
ABSTRACT Some ocular diseases characterized by apoptotic death of retinal ganglion cells (RGCs) and Alzheimer's disease (AD) are chronic neurodegenerative disorders and have similarities in neuropathology. Humanin (HN) is known for its ability to suppress neuronal death induced by AD-related insults. In present study, we investigated the neuroprotective effects of HN on hypoxia-induced toxicity in RGC-5 cells. Hypoxia mimetic compound cobalt chloride (CoCl₂) could increase the cell viability loss and apoptosis, whereas HN can significantly attenuate these effects. This finding may provide new therapeutics for the retinal neurodegenerative diseases targeting neuroprotection.
- SourceAvailable from: ncbi.nlm.nih.gov[show abstract] [hide abstract]
ABSTRACT: Humanin (HN) inhibits neuronal death induced by various Alzheimer's disease (AD)-related insults via an unknown receptor on cell membranes. Our earlier study indicated that the activation of STAT3 was essential for HN-induced neuroprotection, suggesting that the HN receptor may belong to the cytokine receptor family. In this study, a series of loss-of-function tests indicated that gp130, the common subunit of receptors belonging to the IL-6 receptor family, was essential for HN-induced neuroprotection. Overexpression of ciliary neurotrophic factor receptor alpha (CNTFR) and/or the IL-27 receptor subunit, WSX-1, but not that of any other tested gp130-related receptor subunit, up-regulated HN binding to neuronal cells, whereas siRNA-mediated knockdown of endogenous CNTFR and/or WSX-1 reduced it. These results suggest that both CNTFR and WSX-1 may be also involved in HN binding to cells. Consistent with these results, loss-of-functions of CNTFR or WSX-1 in neuronal cells nullified their responsiveness to HN-mediated protection. In vitro-reconstituted binding assays showed that HN, but not the other control peptide, induced the hetero-oligomerization of CNTFR, WSX-1, and gp130. Together, these results indicate that HN protects neurons by binding to a complex or complexes involving CNTFR/WSX-1/gp130.Molecular biology of the cell 05/2009; 20(12):2864-73. · 5.98 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Humanin (HN) was originally identified as an endogenous peptide that protects neuronal cells from apoptosis by mutant Alzheimer's disease genes. This 24-residue peptide has been recently shown to suppress apoptosis by interfering with activation of Bcl-2-associated X protein (Bax) in cytosol. In the present study, we showed that HN increases ATP levels in human lymphocytes, muscular TE671 cells, and neural SKN-MC cells, and protects these cells from serum deprivation-induced apoptosis. The suppressed apoptotic death of serum-deprived cells would be explained by the anti-Bax effect of HN; however, HN also increased ATP levels of serum-supplemented cells (non-apoptotic cells), in which Bax is likely to be inactive. This result suggests the presence of a certain mechanism independent of Bax inactivation to increase ATP levels of cells under non-apoptotic condition. By treatment with HN, the ATP levels of lymphocytes from patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) associated with A3243G mutant mtDNA were increased as well, suggesting that HN is able to prevent cells in MELAS from falling into ATP deficiency. Our quantitative PCR findings indicated that the HN-induced increase in ATP may not be a consequence of mitochondrial proliferation, because HN rather suppressed mtDNA replication. This suppression may be important in the treatment of affected cells in MELAS, since the mutant mtDNAs that increase during compensatory mtDNA replication for ATP deficiency cause excessive formation of reactive oxygen species, leading to further energy crisis. We thus propose that HN, which increases cellular ATP levels without inducing mtDNA replication, may be suited for the treatment of MELAS.Neuropeptides 05/2005; 39(2):97-101. · 2.07 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: An unbiased functional screening with brain cDNA library from an Alzheimer's disease (AD) brain identified a novel 24-residue peptide Humanin (HN), which suppresses AD-related neurotoxicity. As the 1567-base cDNA containing the open reading frame (ORF) of HN is 99% identical to mitochondrial 16S ribosomal RNA as well as registered human mRNA, it was elusive whether HN is produced in vivo. Here, we raised anti-HN antibody and found that long cDNAs containing the ORF of HN (HN-ORF) produced the HN peptide in mammalian cells, dependent on the presence of full-length HN-ORF. Immunoblot analysis detected a 3-kDa protein with HN immunoreactivity in the testis and the colon in 3-week-old mice and in the testis in 12-week-old mice. HN immunoreactivity was also detected in an AD brain, but little in normal brains. This study suggests that HN peptide could be produced in vivo, and would provide a novel insight into the pathophysiology of AD.Neuroscience Letters 06/2002; 324(3):227-31. · 2.03 Impact Factor