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Characterizing the protective effects of SHLP2, a mitochondrial-derived peptide, in macular degeneration.

ABSTRACT: Mitochondrial-derived peptides (MDPs) are rapidly emerging therapeutic targets to combat development of neurodegenerative diseases. SHLP2 (small humanin-like peptide 2) is a newly discovered MDP that is coded from the MT-RNR2 (Mitochondrially encoded 16S rRNA) gene in mitochondrial DNA (mtDNA). In the current study, we examined the biological consequences of treatment with exogenously-added SHLP2 in an in vitro human transmitochondrial age-related macular degeneration (AMD) ARPE-19 cell model. In AMD cells, we observed significant down-regulation of the MDP-coding MT-RNR2 gene, and remarkably reduced levels of all five oxidative phosphorylation (OXPHOS) complex I-V protein subunits that are involved in the electron transport chain; these results suggested mitochondrial toxicity and abnormal OXPHOS complex protein subunits' levels in AMD cells. However, treatment of AMD cells with SHLP2: (1) restored the normal levels of OXPHOS complex protein subunits, (2) prevented loss of viable cells and mitochondria, (3) increased the number of mtDNA copies, (4) induced anti-apoptotic effects, and (5) attenuated amyloid-?-induced cellular and mitochondrial toxicity. Cumulatively, our findings established the protective role of SHLP2 in AMD cells in vitro. In conclusion, this novel study supports the merit of SHLP2 in the treatment of AMD, a primary retinal disease that is a leading cause of blindness among the elderly population in the United States as well as worldwide.

SUBMITTER: Nashine S

PROVIDER: S-EPMC6182005 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Characterizing the protective effects of SHLP2, a mitochondrial-derived peptide, in macular degeneration.

Nashine Sonali S Cohen Pinchas P Nesburn Anthony B AB Kuppermann Baruch D BD Kenney M Cristina MC

Scientific reports 20181011 1

Mitochondrial-derived peptides (MDPs) are rapidly emerging therapeutic targets to combat development of neurodegenerative diseases. SHLP2 (small humanin-like peptide 2) is a newly discovered MDP that is coded from the MT-RNR2 (Mitochondrially encoded 16S rRNA) gene in mitochondrial DNA (mtDNA). In the current study, we examined the biological consequences of treatment with exogenously-added SHLP2 in an in vitro human transmitochondrial age-related macular degeneration (AMD) ARPE-19 cell model. I ...[more]

PMID: 30310092

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Project description:Background: Age-related macular degeneration (AMD) is a leading cause of blindness in the ageing population. Without effective treatment strategies that can prevent disease progression, there is an urgent need for novel therapeutic interventions to reduce the burden of vision loss and improve patients' quality of life. Dysfunctional innate immune responses to oxidative stress observed in AMD can be caused by the formation of oxidised lipids, whilst polyunsaturated fatty acids have shown to increase the risk of AMD and disease progression in affected individuals. Previously, our laboratory has shown that the vegetable-derived isothiocyanate, L-sulforaphane (LSF), can protect human adult pigment epithelial cells from oxidative damage by upregulating gene expression of the oxidative stress enzyme Glutathione-S-Transferase µ1. This study aims to validate the protective effects of LSF on human retinal cells under oxidative stress conditions and to reveal the key players in fatty acid and lipid metabolism that may facilitate this protection. Methods: The in vitro oxidative stress model of AMD was based on the exposure of an adult retinal pigment epithelium-19 cell line to 200µM hydrogen peroxide. Percentage cell proliferation following LSF treatment was measured using tetrazolium salt-based assays. Untargeted fatty acid profiling was performed by gas chromatography-mass spectrometry. Untargeted lipid profiling was performed by liquid chromatography-mass spectrometry. Results: Under hydrogen peroxide-induced oxidative stress conditions, LSF treatment induced dose-dependent cell proliferation. The key fatty acids that were increased by LSF treatment of the retinal cells include oleic acid and eicosatrienoic acid. LSF treatment also increased levels of the lipid classes phosphatidylcholine, cholesteryl ester and oxo-phytodienoic acid but decreased levels of phosphatidylethanolamine lipids. Conclusions: We propose that retinal cells at risk of oxidative damage and apoptosis can be pre-conditioned with LSF to regulate levels of selected fatty acids and lipids known to be implicated in the pathogenesis and progression of AMD.

Project description:ImportanceThe association of major lipid genes with and their potential as drug targets for age-related macular degeneration (AMD) is unknown. These associations are important to study because AMD is the leading cause of irreversible late-onset blindness in high-income countries.ObjectiveTo determine whether the full range of structural genetic variation in apolipoprotein E (APOE), a master gene in peripheral and cerebral lipid metabolism, is associated with risk of AMD.Design, setting, and participantsThis cohort study used data from the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS) cohorts. Participants were followed from study inclusion at the time of blood sampling to occurrence of event, death, emigration, or December 7, 2018, whichever came first. For participants in CCHS, the APOE gene was sequenced, and 9 variants with a heterozygote frequency of at least 0.0002 were genotyped in the CGPS. Observers were masked to patient groupings. Data were analyzed from March to September 2021.ExposuresThe exposure was APOE status, and the direct gene product in plasma, apoE levels, was measured in all participants.Main outcomes and measuresCox regression was applied to estimate risk of AMD associated with APOE genotype.ResultsA total of 105 546 participants (mean [SD] age, 57.7 [13.4] years; 58 140 [55%] female participants) were included. Compared with participants with the common ɛ33 genotype, risk of AMD was lower in participants with ε44 (multifactorially adjusted hazard ratio [aHR], 0.66; 95% CI, 0.45-0.96) and ε43 (aHR, 0.80; 95% CI, 0.71-0.90) genotypes and higher in the ε32 (aHR, 1.15; 95% CI, 1.00-1.31) genotype. Compared with noncarriers, risk of AMD was higher for participants with Gly145Asp (aHR, 3.53; 95% CI, 1.14-10.96) and Arg154Cys (aHR, 4.52; 95% CI, 1-13-18.13) heterozygotes. Results were similar after further adjustment for lipid traits and after adjustment for the APOE ε2/ε3/ε4 variant. Combining all common and rare structural variants in a weighted allele score, risk of AMD per 1-mg/dL genetically higher plasma apoE was increased in the adjusted model (aHR, 1.12; 95% CI, 1.05-1.19), the adjusted model plus APOE ɛ2/ɛ3/ɛ4 status (aHR, 1.82; 95% CI, 1.20-2.76), and the adjusted model in individuals with the ε33 genotype only (aHR, 1.77; 95% CI, 1.14-2.75).Conclusions and relevanceThese findings highlight that structural variation in APOE beyond the ε2/ε3/ε4 variants may be important for risk of AMD in a population of European ancestry. Rare functional ɛ2-like variants in APOE have previously been reported to have protective associations for Alzheimer disease but the present findings suggest a simultaneous high risk of AMD. This would limit the drug target potential of mechanisms resembling these variants.

Project description:PurposeAge-related macular degeneration (AMD) is the leading cause of blindness among older adults, in which oxidative damage may play a pivotal role. Paraoxonase 1 (PON1) protects against oxidative damage and has been evaluated for its involvement in aging diseases including AMD. This study investigated whether PON1 gene polymorphisms associate with AMD.DesignCase-control association study.MethodsWe studied 1037 individuals with AMD subcategorized using AREDS criteria and 370 control subjects without retinal disease. Participants were primarily Caucasian of European descent. All exons of PON1 were evaluated by single-strand conformation polymorphism and direct sequence analysis.ResultsSix missense changes (Leu55Met, Met127Arg, His155Arg, Gln192Arg, Gln192Glu, Ala252Gly) were identified in PON1. We observed a weak association of Leu55Met with an increased risk of wet AMD (P = .02), but not with dry AMD or when combining all patient categories. A significantly higher allele frequency for Gln192Arg was detected in controls than in the combined AMD patient population (P < .0001), and when category 2, 3, and 4 patients were separately considered (P = .004, P = .002, and P < .0001, respectively). For category 4 AMD, the Arg192 allele was significantly less prevalent in the wet form (P < .0001), but not in the dry form (P = .377).ConclusionWe report a weak association of PON1 Leu55Met with an increased risk of wet AMD, replicating previous reports. Our findings indicate a protective role for Gln192Arg, particularly for patients with the wet form. Gln192Glu warrants consideration, as this variant alters the same amino acid as Gln192Arg and was identified only in category 4 AMD patients. We believe that Met127Arg, His155Arg, and Ala252Gly play minor roles in AMD susceptibility because of their limited frequency and/or location within the PON1 gene. The functional and biological mechanism by which Gln192Arg is acting to decrease AMD susceptibility remains to be determined.

Dataset Information

Characterizing the protective effects of SHLP2, a mitochondrial-derived peptide, in macular degeneration.

Publications

Characterizing the protective effects of SHLP2, a mitochondrial-derived peptide, in macular degeneration.

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