The Experts below are selected from a list of 2892 Experts worldwide ranked by ideXlab platform
Rochelle Buffenstein - One of the best experts on this subject based on the ideXlab platform.
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Naked Mole-Rat, a Rodent with an Apolipoprotein A-I Dimer.
Lipids, 2020Co-Authors: Don L. Puppione, Denise P. Tran, Muhammad A. Zenaidee, Sarada Charugundla, Julian P. Whitelegge, Rochelle BuffensteinAbstract:A variety of rodents have been used as experimental animals in metabolic studies of plasma lipids and lipoproteins. These studies have included understanding the functional role of apolipoprotein A-I, the major protein on the surface of HDL. Reviewing the genomic database for entries for rodent apoA-I genes, it was discovered that the Naked Mole-Rat (Heterocephalus glaber) gene encoded a protein with a cysteine at residue 28. Previously, two cases have been reported in which human heterozygotes had apoA-I with cysteine at residues 173 (apoA-I Milano) or at 151 (apoA-I Paris). Interestingly, both groups, in spite of having low levels of HDL and modeRately elevated plasma triacylglycerols, had no evidence of cardiovascular disease. Moreover, the presence of the cysteine enabled the apoA-I to form both homodimers and heterodimers. Prior to this report, no other mammalian apoA-I has been found with a cysteine in its sequence. In addition, the encoded Naked Mole-Rat protein had different amino acids at sites that were conserved in all other mammals. These differences resulted in Naked Mole-Rat apoA-I having an unexpected neutral pI value, whereas other mammalian apoA-I have negative pI values. To verify these sequence differences and to determine if the N-terminal location of C28 precluded dimer formation, we conducted mass spectrometry analyses of apoA-I and other proteins associated with HDL. Consistent with the genomic data, our analyses confirmed the presence of C28 and the formation of a homodimer. Analysis of plasma lipids surprisingly revealed a profile similar to the human heterozygotes.
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Unprovoked Stabilization and Nuclear Accumulation of the Naked Mole-Rat p53 Protein.
Scientific reports, 2020Co-Authors: Marian M Deuker, Kaitlyn N. Lewis, Rochelle Buffenstein, Maria Ingaramo, Jacob C. Kimmel, Jeff SettlemanAbstract:The Naked Mole-Rat is a subterranean rodent, approximately the size of a mouse, renowned for its exceptional longevity (>30 years) and remarkable resistance to cancer. To explore putative mechanisms underlying the cancer resistance of the Naked Mole-Rat, we investigated the regulation and function of the most commonly mutated tumor suppressor, TP53, in the Naked Mole-Rat. We found that the p53 protein in Naked Mole-Rat embryonic fibroblasts (NEFs) exhibits a half-life more than ten times in excess of the protein's characterized half-life in mouse and human embryonic fibroblasts. We determined that the long half-life of the Naked Mole-Rat p53 protein reflects protein-extrinsic regulation. Relative to mouse and human p53, a larger proportion of Naked Mole-Rat p53 protein is constitutively localized in the nucleus prior to DNA damage. Nevertheless, DNA damage is sufficient to induce activation of canonical p53 target genes in NEFs. Despite the uniquely long half-life and unprecedented basal nuclear localization of p53 in NEFs, Naked Mole-Rat p53 retains its canonical tumor suppressive activity. Together, these findings suggest that the unique stabilization and regulation of the p53 protein may contribute to the Naked Mole-Rat's remarkable resistance to cancer.
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Naked Mole-Rat mortality Rates defy Gompertzian laws by not increasing with age
eLife, 2018Co-Authors: J. Graham Ruby, Megan Smith, Rochelle BuffensteinAbstract:The longest-lived rodent, the Naked Mole-Rat (Heterocephalus glaber), has a reported maximum lifespan of >30 years and exhibits delayed and/or attenuated age-associated physiological declines. We questioned whether these mouse-sized, eusocial rodents conform to Gompertzian mortality laws by experiencing an exponentially increasing risk of death as they get older. We compiled and analyzed a large compendium of historical Naked Mole-Rat lifespan data with >3000 data points. Kaplan-Meier analyses revealed a substantial portion of the population to have survived at 30 years of age. Moreover, unlike all other mammals studied to date, and regardless of sex or breeding-status, the age-specific hazard of mortality did not increase with age, even at ages 25-fold past their time to reproductive maturity. This absence of hazard increase with age, in defiance of Gompertz's law, uniquely identifies the Naked Mole-Rat as a non-aging mammal, confirming its status as an exceptional model for biogerontology.
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The Naked Mole-Rat exhibits an unusual cardiac myofilament protein profile providing new insights into heart function of this naturally subterranean rodent
Pflugers Archiv : European journal of physiology, 2017Co-Authors: Kelly M. Grimes, Susan T. Weintraub, David Y. Barefield, Mohit Kumar, Pieter P. De Tombe, Sakthivel Sadayappan, James W. Mcnamara, Rochelle BuffensteinAbstract:The long-lived, hypoxic-tolerant Naked Mole-Rat well-maintains cardiac function over its three-decade-long lifespan and exhibits many cardiac features atypical of similar-sized laboRatory rodents. For example, they exhibit low heart Rates and resting cardiac contractility, yet have a large cardiac reserve. These traits are considered ecophysiological adaptations to their dank subterranean atmosphere of low oxygen and high carbon dioxide levels and may also contribute to negligible declines in cardiac function during aging. We asked if Naked Mole-Rats had a different myofilament protein signature to that of similar-sized mice that commonly show both high heart Rates and high basal cardiac contractility. Adult mouse ventricles predominantly expressed α-myosin heavy chain (97.9 ± 0.4%). In contrast, and more in keeping with humans, β myosin heavy chain was the dominant isoform (79.0 ± 2.0%) in Naked Mole-Rat ventricles. Naked Mole-Rat ventricles diverged from those of both humans and mice, as they expressed both cardiac and slow skeletal isoforms of troponin I. This myofilament protein profile is more commonly observed in mice in utero and during cardiomyopathies. There were no species differences in phosphorylation of cardiac myosin binding protein-C or troponin I. Phosphorylation of both ventricular myosin light chain 2 and cardiac troponin T in Naked Mole-Rats was approximately half that observed in mice. Myofilament function was also compared between the two species using permeabilized cardiomyocytes. Together, these data suggest a cardiac myofilament protein signature that may contribute to the Naked Mole-Rat’s suite of adaptations to its natural subterranean habitat.
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Unraveling the message: insights into compaRative genomics of the Naked Mole-Rat
Mammalian Genome, 2016Co-Authors: Kaitlyn N. Lewis, Ilya Soifer, Eugene Melamud, R. Scott Mcisaac, Matthew Hibbs, Rochelle BuffensteinAbstract:Animals have evolved to survive, and even thrive, in different environments. Genetic adaptations may have indirectly created phenotypes that also resulted in a longer lifespan. One example of this phenomenon is the preternaturally long-lived Naked Mole-Rat. This strictly subterranean rodent toleRates hypoxia, hypercapnia, and soil-based toxins. Naked Mole-Rats also exhibit pronounced resistance to cancer and an attenuated decline of many physiological characteristics that often decline as mammals age. Elucidating mechanisms that give rise to their unique phenotypes will lead to better understanding of subterranean ecophysiology and biology of aging. CompaRative genomics could be a useful tool in this regard. Since the publication of a Naked Mole-Rat genome assembly in 2011, analyses of genomic and transcriptomic data have enabled a clearer understanding of Mole-Rat evolutionary history and suggested Molecular pathways (e.g., NRF2-signaling activation and DNA damage repair mechanisms) that may explain the extraordinarily longevity and unique health traits of this species. However, careful scrutiny and re-analysis suggest that some identified features result from incorrect or imprecise annotation and assembly of the Naked Mole-Rat genome: in addition, some of these conclusions (e.g., genes involved in cancer resistance and hairlessness) are rejected when the analysis includes additional, more closely related species. We describe how the combination of better study design, improved genomic sequencing techniques, and new bioinformatic and data analytical tools will improve compaRative genomics and ultimately bridge the gap between traditional model and nonmodel organisms.
Ewan St John Smith - One of the best experts on this subject based on the ideXlab platform.
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Cholesterol-rich Naked Mole-Rat brain lipid membranes are susceptible to amyloid beta-induced damage in vitro
Aging, 2020Co-Authors: Paulina Urriola-munoz, Ewan St John Smith, Daniel Frankel, Matthew Davies, Bharat Bhushan, Yavuz Kulaberoglu, Justine Bertrand-michel, Melissa Pergande, Andrew SmithAbstract:Naked Mole-Rats are extraordinarily long-lived rodents that offer unique opportunities to study the Molecular origins of age-related neurodegeneRative diseases. Remarkably, they do not accumulate amyloid plaques, even though their brains contain high concentRations of amyloid beta (Aβ) peptide from a young age. Therefore, they represent a particularly favourable organism to study the mechanisms of resistance against Aβ neurotoxicity. Here we examine the composition, phase behaviour, and Aβ interactions of Naked Mole-Rat brain lipids. Relative to mouse, Naked Mole-Rat brain lipids are rich in cholesterol and contain sphingomyelin in lower amounts and of shorter chain lengths. Proteins associated with the metabolism of ceramides, sphingomyelins and sphingosine-1-phosphate receptor 1 were also found to be decreased in Naked Mole-Rat brain lysates. Correspondingly, we find that Naked Mole-Rat brain lipid membranes exhibit a high degree of phase sepaRation, with the liquid ordered phase extending to 80% of the supported lipid bilayer. These observations are consistent with the 'membrane pacemaker' hypothesis of ageing, according to which long-living species have lipid membranes particularly resistant to oxidative damage. We also found that exposure to Aβ disrupts Naked Mole-Rat brain lipid membranes significantly, breaking the membrane into pieces while mouse brain derived lipids remain largely intact upon Aβ exposure.
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cholesterol rich highly phase sepaRated Naked Mole Rat brain lipids are exquisitely sensitive to amyloid induced membrane damage
bioRxiv, 2020Co-Authors: Daniel Frankel, Ewan St John Smith, Yavuz Kulaberoglu, Kenneth S Rankin, Nicolas Cenac, Matt Davies, Janet R Kumita, Michele Vendruscolo, Paulina Urriola Munoz, Justine BertrandmichelAbstract:Naked Mole-Rats do not develop neurodegeneRative diseases associated with ageing and their brains are devoid of amyloid plaques. However, even the young Naked Mole-Rat brain contains high concentRations of amyloid beta peptide. Thus, the question arises, how do Naked Mole-Rat brain cell membranes survive in this amyloid rich environment? In this work we examine the composition, phase behaviour, and amyloid beta interactions of Naked Mole-Rat brain lipids. Relative to mouse, Naked Mole-Rat brain lipids are rich in cholesterol and contain less sphingomyelin, the sphingomyelin present being of a characteristic short chain length. We find that Naked Mole-Rat brain lipid membranes exhibit an extremely high degree of phase sepaRation, consistent with the membrane pacemaker hypothesis of ageing, with the liquid ordered phase occupying up to 80 % of the supported lipid bilayer. Exposure of mouse brain lipids to human amyloid beta at physiologically relevant concentRations leads to small, well-defined footprints, whereby the amyloid beta has sunk into the membrane. Under the same exposure regime, the Naked Mole-Rat brain lipid membranes are destroyed, leaving only membrane fragments in place of the intact membrane. These results suggest that Naked Mole-Rats have likely developed additional neuroprotective mechanisms to limit cellular damage because by considering lipids alone brain tissue should not be able to survive in such a toxic environment.
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Naked Mole-Rat acid-sensing ion channel 3 forms nonfunctional homomers, but functional heteromers.
The Journal of biological chemistry, 2017Co-Authors: Laura-nadine Schuhmacher, Gerard Callejo, Shyam Srivats, Ewan St John SmithAbstract:Prism files of analysed data for Naked Mole-Rat acid-sensing ion channel 3 forms nonfunctional homomers, but functional heteromers
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Naked Mole-Rat acid-sensing ion channel 3 forms nonfunctional homomers, but functional heteromers.
The Journal of biological chemistry, 2017Co-Authors: Laura-nadine Schuhmacher, Gerard Callejo, Shyam Srivats, Ewan St John SmithAbstract:Acid-sensing ion channels (ASICs) form both homotrimeric and heterotrimeric ion channels that are activated by extracellular protons and are involved in a wide range of physiological and pathophysiological processes, including pain and anxiety. ASIC proteins can form both homotrimeric and heterotrimeric ion channels. The ASIC3 subunit has been shown to be of particular importance in the peripheral nervous system with pharmacological and genetic manipulations demonstRating a role in pain. Naked Mole-Rats, despite having functional ASICs, are insensitive to acid as a noxious stimulus and show diminished avoidance of acidic fumes, ammonia, and carbon dioxide. Here we cloned Naked Mole-Rat ASIC3 (nmrASIC3) and used a cell-surface biotinylation assay to demonstRate that it traffics to the plasma membrane, but using whole-cell patch clamp electrophysiology we observed that nmrASIC3 is insensitive to both protons and the non-proton ASIC3 agonist 2-guanidine-4-methylquinazoline. However, in line with previous reports of ASIC3 mRNA expression in dorsal root ganglia neurons, we found that the ASIC3 antagonist APETx2 reversibly inhibits ASIC-like currents in Naked Mole-Rat dorsal root ganglia neurons. We further show that like the proton-insensitive ASIC2b and ASIC4, nmrASIC3 forms functional, proton-sensitive heteromers with other ASIC subunits. An amino acid alignment of ASIC3s between 9 relevant rodent species and human identified unique sequence differences that might underlie the proton insensitivity of nmrASIC3. However, introducing nmrASIC3 differences into Rat ASIC3 (rASIC3) produced only minor differences in channel function, and replacing the nmrASIC3 sequence with that of rASIC3 did not produce a proton-sensitive ion channel. Our observation that nmrASIC3 forms nonfunctional homomers may reflect a further adaptation of the Naked Mole-Rat to living in an environment with high-carbon dioxide levels.
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Naked Mole-Rat acid-sensing ion channel 3 forms non-functional homomers, but functional heteromers
2017Co-Authors: Laura-nadine Schuhmacher, Gerard Callejo, Shyam Srivats, Ewan St John SmithAbstract:Acid-sensing ion channels (ASICs) form both homotrimeric and heterotrimeric ion channels that are activated by extracellular protons and are involved in a wide range of physiological and pathophysiological processes, including pain and anxiety. ASIC proteins can form both homotrimeric and heterotrimeric ion channels. The ASIC3 subunit has been shown to be of particular importance in the peripheral nervous system with pharmacological and genetic manipulations demonstRating a role in pain. Naked Mole-Rats, despite having functional ASICs, are insensitive to acid as a noxious stimulus and show diminished avoidance of acidic fumes, ammonia and carbon dioxide. Here we cloned Naked Mole-Rat ASIC3 (nmrASIC3) and used a cell surface biotinylation assay to demonstRate that it traffics to the plasma membrane, but using whole-cell patch-lamp electrophysiology we observed that nmrASIC3 is insensitive to both protons and the non-proton ASIC3 agonist 2-Guanidine-4-methylquinazoline (GMQ). However, in line with previous reports of ASIC3 mRNA expression in dorsal root ganglia (DRG) neurons, we found that the ASIC3 antagonist APETx2 reversibly inhibits ASIC-like currents in Naked Mole-Rat DRG neurons. We further show that like the proton-insensitive ASIC2b and ASIC4, nmrASIC3 forms functional, proton sensitive heteromers with other ASIC subunits. An amino acid alignment of ASIC3s between 9 relevant rodent species and human identified unique sequence differences that might underlie the proton insensitivity of nmrASIC3. However, introducing nmrASIC3 differences into Rat ASIC3 (rASIC3) produced only minor differences in channel function, and replacing nmrASIC3 sequence with that of rASIC3 did not produce a proton-sensitive ion channel. Our observation that nmrASIC3 forms nonfunctional homomers may reflect a further adaptation of the Naked Mole-Rat to living in an environment with high-carbon dioxide levels.
Andrei Seluanov - One of the best experts on this subject based on the ideXlab platform.
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ink4 locus of the tumor resistant rodent the Naked Mole Rat expresses a functional p15 p16 hybrid isoform
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Xiao Tian, Jorge Azpurua, Adeline Augereau, Zhonghe Ke, Zhengdong D Zhang, Vera Gorbunova, Jan Vijg, Vadim N. Gladyshev, Andrei SeluanovAbstract:The Naked Mole Rat (Heterocephalus glaber) is a long-lived and tumor-resistant rodent. Tumor resistance in the Naked Mole Rat is mediated by the extracellular matrix component hyaluronan of very high Molecular weight (HMW-HA). HMW-HA triggers hypersensitivity of Naked Mole Rat cells to contact inhibition, which is associated with induction of the INK4 (inhibitors of cyclin dependent kinase 4) locus leading to cell-cycle arrest. The INK4a/b locus is among the most frequently mutated in human cancer. This locus encodes three distinct tumor suppressors: p15INK4b, p16INK4a, and ARF (alternate reading frame). Although p15INK4b has its own ORF, p16INK4a and ARF share common second and third exons with alternative reading frames. Here, we show that, in the Naked Mole Rat, the INK4a/b locus encodes an additional product that consists of p15INK4b exon 1 joined to p16INK4a exons 2 and 3. We have named this isoform pALTINK4a/b (for alternative splicing). We show that pALTINK4a/b is present in both cultured cells and Naked Mole Rat tissues but is absent in human and mouse cells. Additionally, we demonstRate that pALTINK4a/b expression is induced during early contact inhibition and upon a variety of stresses such as UV, gamma irradiation-induced senescence, loss of substRate attachment, and expression of oncogenes. When overexpressed in Naked Mole Rat or human cells, pALTINK4a/b has stronger ability to induce cell-cycle arrest than either p15INK4b or p16INK4a. We hypothesize that the presence of the fourth product, pALTINK4a/b of the INK4a/b locus in the Naked Mole Rat, contributes to the increased resistance to tumorigenesis of this species.
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INK4 locus of the tumor-resistant rodent, the Naked Mole Rat, expresses a functional p15/p16 hybrid isoform.
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Xiao Tian, Jorge Azpurua, Adeline Augereau, Zhengdong D Zhang, Vera Gorbunova, Jan Vijg, Vadim N. Gladyshev, Andrei SeluanovAbstract:The Naked Mole Rat (Heterocephalus glaber) is a long-lived and tumor-resistant rodent. Tumor resistance in the Naked Mole Rat is mediated by the extracellular matrix component hyaluronan of very high Molecular weight (HMW-HA). HMW-HA triggers hypersensitivity of Naked Mole Rat cells to contact inhibition, which is associated with induction of the INK4 (inhibitors of cyclin dependent kinase 4) locus leading to cell-cycle arrest. The INK4a/b locus is among the most frequently mutated in human cancer. This locus encodes three distinct tumor suppressors: p15INK4b, p16INK4a, and ARF (alternate reading frame). Although p15INK4b has its own ORF, p16INK4a and ARF share common second and third exons with alternative reading frames. Here, we show that, in the Naked Mole Rat, the INK4a/b locus encodes an additional product that consists of p15INK4b exon 1 joined to p16INK4a exons 2 and 3. We have named this isoform pALTINK4a/b (for alternative splicing). We show that pALTINK4a/b is present in both cultured cells and Naked Mole Rat tissues but is absent in human and mouse cells. Additionally, we demonstRate that pALTINK4a/b expression is induced during early contact inhibition and upon a variety of stresses such as UV, gamma irradiation-induced senescence, loss of substRate attachment, and expression of oncogenes. When overexpressed in Naked Mole Rat or human cells, pALTINK4a/b has stronger ability to induce cell-cycle arrest than either p15INK4b or p16INK4a. We hypothesize that the presence of the fourth product, pALTINK4a/b of the INK4a/b locus in the Naked Mole Rat, contributes to the increased resistance to tumorigenesis of this species.
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The Naked Mole Rat Genome Resource : facilitating analyses of cancer and longevity-related adaptations
Bioinformatics (Oxford England), 2014Co-Authors: Michael Keane, Andrei Seluanov, Vera Gorbunova, Thomas Craig, Jessica Alföldi, Aaron M. Berlin, Jeremy Johnson, Federica Di Palma, Kerstin Lindblad-toh, George M. ChurchAbstract:Motivation: The Naked Mole Rat (Heterocephalus glaber )i s an exceptionally long-lived and cancer-resistant rodent native to East Africa. Although its genome was previously sequenced, here we report a new assembly sequenced by us with substantially higher N50 values for scaffolds and contigs. Results: We analyzed the annotation of this new improved assembly and identified candidate genomic adaptations which may have contributed to the evolution of the Naked Mole Rat’s extraordinary traits, including in regions of p53, and the hyaluronan receptors CD44 and HMMR (RHAMM). Furthermore, we developed a freely available web portal, the Naked Mole Rat Genome Resource (http://www.NakedMole-Rat.org), featuring the data and results of our analysis, to assist researchers interested in the genome and genes of the Naked Mole Rat, and also to facilitate further studies on this fascinating species. Availability and implementation: The Naked Mole Rat Genome Resource is freely available online at http://www.Naked-Mole-Rat.org. This resource is open source and the source code is available at
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Naked Mole Rat has increased translational fidelity compared with the mouse as well as a unique 28s ribosomal rna cleavage
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Jorge Azpurua, Zhonghe Ke, Zhengdong D Zhang, Vera Gorbunova, Iris X Chen, Quanwei Zhang, Dmitri N Ermolenko, Andrei SeluanovAbstract:The Naked Mole-Rat (Heterocephalus glaber) is a subterranean eusocial rodent with a markedly long lifespan and resistance to tumorigenesis. Multiple data implicate modulation of protein translation in longevity. Here we report that 28S ribosomal RNA (rRNA) of the Naked Mole-Rat is processed into two smaller fragments of unequal size. The two breakpoints are located in the 28S rRNA divergent region 6 and excise a fragment of 263 nt. The excised fragment is unique to the Naked Mole-Rat rRNA and does not show homology to other genomic regions. Because this hidden break site could alter ribosome structure, we investigated whether translation Rate and amino acid incorpoRation fidelity were altered. We report that Naked Mole-Rat fibroblasts have significantly increased translational fidelity despite having comparable translation Rates with mouse fibroblasts. Although we cannot directly test whether the unique 28S rRNA structure contributes to the increased fidelity of translation, we speculate that it may change the folding or dynamics of the large ribosomal subunit, altering the Rate of GTP hydrolysis and/or interaction of the large subunit with tRNA during accommodation, thus affecting the fidelity of protein synthesis. In summary, our results show that Naked Mole-Rat cells produce fewer aberrant proteins, supporting the hypothesis that the more stable proteome of the Naked Mole-Rat contributes to its longevity.
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High-Molecular-mass hyaluronan mediates the cancer resistance of the Naked Mole Rat
Nature, 2013Co-Authors: Xiao Tian, Max Myakishev-rempel, Julia Ablaeva, Christopher Hine, Amita Vaidya, Jorge Azpurua, Vera Gorbunova, Eviatar Nevo, Andrei SeluanovAbstract:Naked Mole Rats seem almost entirely protected from developing cancer, and this can now, at least in part, be explained by the production of a unique high-Molecular-mass form of hyaluronan, a component of the extracellular matrix; together with an increased sensitivity of Naked Mole-Rat cells to hyaluronan signalling, this form protects its cells from oncogenic transformation. The Naked Mole Rat ( Heterocephalus glaber ) displays exceptional longevity, with a maximum lifespan exceeding 30 years^ 1 , 2 , 3 . This is the longest reported lifespan for a rodent species and is especially striking considering the small body mass of the Naked Mole Rat. In comparison, a similarly sized house mouse has a maximum lifespan of 4 years^ 4 , 5 . In addition to their longevity, Naked Mole Rats show an unusual resistance to cancer. Multi-year observations of large Naked Mole-Rat colonies did not detect a single incidence of cancer^ 2 , 6 . Here we identify a mechanism responsible for the Naked Mole Rat’s cancer resistance. We found that Naked Mole-Rat fibroblasts secrete extremely high-Molecular-mass hyaluronan (HA), which is over five times larger than human or mouse HA. This high-Molecular-mass HA accumulates abundantly in Naked Mole-Rat tissues owing to the decreased activity of HA-degrading enzymes and a unique sequence of hyaluronan synthase 2 ( HAS2 ). Furthermore, the Naked Mole-Rat cells are more sensitive to HA signalling, as they have a higher affinity to HA compared with mouse or human cells. Perturbation of the signalling pathways sufficient for malignant transformation of mouse fibroblasts fails to transform Naked Mole-Rat cells. However, once high-Molecular-mass HA is removed by either knocking down HAS2 or overexpressing the HA-degrading enzyme, HYAL2, Naked Mole-Rat cells become susceptible to malignant transformation and readily form tumours in mice. We speculate that Naked Mole Rats have evolved a higher concentRation of HA in the skin to provide skin elasticity needed for life in underground tunnels. This trait may have then been co-opted to provide cancer resistance and longevity to this species. Naked Mole Rats are remarkable in combining extreme longevity with virtually complete resistance to cancer. Now a novel glycosaminoglycan variant that may have evolved to provide the creatures with the tough, flexible skin needed for a subterranean lifestyle has been identified as a key contributor to their cancer resistance. Hyaluronan, or hyaluronic acid, is a ubiquitous component of the extracellular matrix. Xiao Tian et al . observed that the culture media of Naked Mole-Rat fibroblasts becomes viscous owing to the accumulation of a thick 'gooey' substance and identified it as a high-Molecular-mass hyaluronan (HMM-HA), more than five times larger than mouse and human equivalents. It accumulates in Naked Mole-Rat tissues owing to low hyaluronidase activity and a unique form of hyaluronan synthase 2. HMM-HA acts through the CD44 receptor and removal of HMM-HA makes Naked Mole-Rat cells more susceptible to transformation. This unusual model of cancer protection suggests potential new avenues of research into anticancer and life-extension stRategies.
Thomas J Park - One of the best experts on this subject based on the ideXlab platform.
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Auditory-vocal coupling in the Naked Mole-Rat, a mammal with poor auditory thresholds
Journal of Comparative Physiology A, 2018Co-Authors: Kazuo Okanoya, Shigeto Yosida, Catherine M. Barone, Daniel T. Applegate, Elizabeth F. Brittan-powell, Robert J. Dooling, Thomas J ParkAbstract:Naked Mole-Rats are extremely social and extremely vocal rodents, displaying a wide range of functionally distinct call types and vocalizing almost continuously. Their vocalizations are low frequency, and a behavioral audiogram has shown that Naked Mole-Rats, like other subterranean mammals, hear only low frequencies. Hence, the frequency range of their hearing and vocalizations appears to be well matched. However, even at low frequencies, Naked Mole-Rats show very poor auditory thresholds, suggesting vocal communication may be effective only over short distances. However, in a tunnel environment where low frequency sounds propagate well and background noise is low, it may be that vocalizations travel considerable distances at supRathreshold intensities. Here, we confirmed hearing sensitivity using the auditory brainstem response; we characterized signature and alarm calls in intensity and frequency domains and we measured the effects of propagation through tubes with the diameter of Naked Mole-Rat tunnels. Signature calls—used for intimate communication—could travel 3–8 m at supRathreshold intensities, and alarm calls (lower frequency and higher intensity), could travel up to 15 m. Despite this species’ poor hearing sensitivity, the Naked Mole-Rat displays a functional, coupled auditory-vocal communication system—a hallmark principle of acoustic communication systems across taxa.
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fructose driven glycolysis supports anoxia resistance in the Naked Mole Rat
Science, 2017Co-Authors: Thomas J Park, Jane Reznick, Bethany L Peterson, Damir Omerbasic, Nigel C Bennett, Henning P J L Kuich, Christin Zasada, Brigitte M Browe, Gregory R C Blass, Wiebke HamannAbstract:The African Naked Mole-Rat’s (Heterocephalus glaber) social and subterranean lifestyle geneRates a hypoxic niche. Under experimental conditions, Naked Mole-Rats toleRate hours of extreme hypoxia and survive 18 minutes of total oxygen deprivation (anoxia) without apparent injury. During anoxia, the Naked Mole-Rat switches to anaerobic metabolism fueled by fructose, which is actively accumulated and metabolized to lactate in the brain. Global expression of the GLUT5 fructose transporter and high levels of ketohexokinase were identified as Molecular signatures of fructose metabolism. Fructose-driven glycolytic respiRation in Naked Mole-Rat tissues avoids feedback inhibition of glycolysis via phosphofructokinase, supporting viability. The metabolic rewiring of glycolysis can circumvent the normally lethal effects of oxygen deprivation, a mechanism that could be harnessed to minimize hypoxic damage in human disease.
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Blunted neuronal calcium response to hypoxia in Naked Mole-Rat hippocampus.
PloS one, 2012Co-Authors: Bethany L Peterson, Thomas J Park, Rochelle Buffenstein, John Larson, Christopher P. FallAbstract:Naked Mole-Rats are highly social and strictly subterranean rodents that live in large communal colonies in sealed and chronically oxygen-depleted burrows. Brain slices from Naked Mole-Rats show extreme tolerance to hypoxia compared to slices from other mammals, as indicated by maintenance of synaptic transmission under more hypoxic conditions and three fold longer latency to anoxic depolarization. A key factor in determining whether or not the cellular response to hypoxia is reversible or leads to cell death may be the elevation of intracellular calcium concentRation. In the present study, we used fluorescent imaging techniques to measure relative intracellular calcium changes in CA1 pyramidal cells of hippocampal slices during hypoxia. We found that calcium accumulation during hypoxia was significantly and substantially attenuated in slices from Naked Mole-Rats compared to slices from laboRatory mice. This was the case for both neonatal (postnatal day 6) and older (postnatal day 20) age groups. Furthermore, while both species demonstRated more calcium accumulation at older ages, the older Naked Mole-Rats showed a smaller calcium accumulation response than even the younger mice. A blunted intracellular calcium response to hypoxia may contribute to the extreme hypoxia tolerance of Naked Mole-Rat neurons. The results are discussed in terms of a general hypothesis that a very prolonged or arrested developmental process may allow adult Naked Mole-Rat brain to retain the hypoxia tolerance normally only seen in neonatal mammals.
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Naked Mole Rat
The Laboratory Rabbit Guinea Pig Hamster and Other Rodents, 2012Co-Authors: Rochelle Buffenstein, Thomas J Park, Martha A. Hanes, James E ArtwohlAbstract:Publisher Summary Naked Mole Rats are mouse-sized rodents that have become an important animal model in biomedical research. They play a unique mammalian role in behavioral and ecophysiological research of life underground. This chapter studies the general physiology, anatomy of organ systems, husbandry, and uses in research of the Naked Mole Rats. Naked Mole Rats belong to the order Rodentia in that they have two incisor teeth on the upper and lower arcade that continuously grow. The skin is loose, wrinkled, and brownish pink in color. The body is for the most part absent of hairs with the exception of tactile hairs that are regularly arranged throughout the body and which are particularly prominent around the face and to a lesser extent on the tail. They are typically housed at 28–30°C, and at 50–60% relative humidity. Because Naked Mole Rats are social and have coopeRative behaviors, the study of their conduct has more applicability to people. The chapter describes the models of experimental research on the Naked Mole Rat such as the model of reproductive suppression, model of somatosensory processing, model of bone elongation, and model of aging.
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Functional neurokinin and NMDA receptor activity in an animal naturally lacking substance P: the Naked Mole-Rat.
PloS one, 2010Co-Authors: Antje Brand, Gary R. Lewin, Ewan St John Smith, Thomas J ParkAbstract:Naked Mole-Rats are extremely unusual among mammals in that their cutaneous C-fibers lack the neuropeptide Substance P (SP). In other mammals, SP plays an important role in nociception: it is released from C-fibers onto spinal neurons where it facilitates NMDA receptor activity and causes sensitization that can last for minutes, hours or days. In the present study, we tested the effects of intRathecal application of: 1) SP, 2) an SP antagonist (GR-82334), and 3) an NMDA antagonist (APV) on heat-evoked foot withdrawal. In the Naked Mole-Rat, at a high enough concentRation, application of SP caused a large, immediate, and long-lasting sensitization of foot withdrawal latency that was transiently reversed by application of either antagonist. However, neither SP nor NMDA antagonists had an effect when administered alone to naive animals. In contrast, both antagonists induced an increase in basal withdrawal latency in mice. These results indicate that spinal neurons in Naked Mole-Rats have functional SP and NMDA receptors, but that these receptors do not participate in heat-evoked foot withdrawal unless SP is experimentally introduced. We propose that the natural lack of SP in Naked Mole-Rat C-fibers may have resulted during adaptation to living in a chronically high carbon dioxide, high ammonia environment that, in other mammals, would stimulate C-fibers and evoke nocifensive behavior.
Laura-nadine Schuhmacher - One of the best experts on this subject based on the ideXlab platform.
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Naked Mole-Rat acid-sensing ion channel 3 forms nonfunctional homomers, but functional heteromers.
The Journal of biological chemistry, 2017Co-Authors: Laura-nadine Schuhmacher, Gerard Callejo, Shyam Srivats, Ewan St John SmithAbstract:Prism files of analysed data for Naked Mole-Rat acid-sensing ion channel 3 forms nonfunctional homomers, but functional heteromers
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Naked Mole-Rat acid-sensing ion channel 3 forms nonfunctional homomers, but functional heteromers.
The Journal of biological chemistry, 2017Co-Authors: Laura-nadine Schuhmacher, Gerard Callejo, Shyam Srivats, Ewan St John SmithAbstract:Acid-sensing ion channels (ASICs) form both homotrimeric and heterotrimeric ion channels that are activated by extracellular protons and are involved in a wide range of physiological and pathophysiological processes, including pain and anxiety. ASIC proteins can form both homotrimeric and heterotrimeric ion channels. The ASIC3 subunit has been shown to be of particular importance in the peripheral nervous system with pharmacological and genetic manipulations demonstRating a role in pain. Naked Mole-Rats, despite having functional ASICs, are insensitive to acid as a noxious stimulus and show diminished avoidance of acidic fumes, ammonia, and carbon dioxide. Here we cloned Naked Mole-Rat ASIC3 (nmrASIC3) and used a cell-surface biotinylation assay to demonstRate that it traffics to the plasma membrane, but using whole-cell patch clamp electrophysiology we observed that nmrASIC3 is insensitive to both protons and the non-proton ASIC3 agonist 2-guanidine-4-methylquinazoline. However, in line with previous reports of ASIC3 mRNA expression in dorsal root ganglia neurons, we found that the ASIC3 antagonist APETx2 reversibly inhibits ASIC-like currents in Naked Mole-Rat dorsal root ganglia neurons. We further show that like the proton-insensitive ASIC2b and ASIC4, nmrASIC3 forms functional, proton-sensitive heteromers with other ASIC subunits. An amino acid alignment of ASIC3s between 9 relevant rodent species and human identified unique sequence differences that might underlie the proton insensitivity of nmrASIC3. However, introducing nmrASIC3 differences into Rat ASIC3 (rASIC3) produced only minor differences in channel function, and replacing the nmrASIC3 sequence with that of rASIC3 did not produce a proton-sensitive ion channel. Our observation that nmrASIC3 forms nonfunctional homomers may reflect a further adaptation of the Naked Mole-Rat to living in an environment with high-carbon dioxide levels.
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Naked Mole-Rat acid-sensing ion channel 3 forms non-functional homomers, but functional heteromers
2017Co-Authors: Laura-nadine Schuhmacher, Gerard Callejo, Shyam Srivats, Ewan St John SmithAbstract:Acid-sensing ion channels (ASICs) form both homotrimeric and heterotrimeric ion channels that are activated by extracellular protons and are involved in a wide range of physiological and pathophysiological processes, including pain and anxiety. ASIC proteins can form both homotrimeric and heterotrimeric ion channels. The ASIC3 subunit has been shown to be of particular importance in the peripheral nervous system with pharmacological and genetic manipulations demonstRating a role in pain. Naked Mole-Rats, despite having functional ASICs, are insensitive to acid as a noxious stimulus and show diminished avoidance of acidic fumes, ammonia and carbon dioxide. Here we cloned Naked Mole-Rat ASIC3 (nmrASIC3) and used a cell surface biotinylation assay to demonstRate that it traffics to the plasma membrane, but using whole-cell patch-lamp electrophysiology we observed that nmrASIC3 is insensitive to both protons and the non-proton ASIC3 agonist 2-Guanidine-4-methylquinazoline (GMQ). However, in line with previous reports of ASIC3 mRNA expression in dorsal root ganglia (DRG) neurons, we found that the ASIC3 antagonist APETx2 reversibly inhibits ASIC-like currents in Naked Mole-Rat DRG neurons. We further show that like the proton-insensitive ASIC2b and ASIC4, nmrASIC3 forms functional, proton sensitive heteromers with other ASIC subunits. An amino acid alignment of ASIC3s between 9 relevant rodent species and human identified unique sequence differences that might underlie the proton insensitivity of nmrASIC3. However, introducing nmrASIC3 differences into Rat ASIC3 (rASIC3) produced only minor differences in channel function, and replacing nmrASIC3 sequence with that of rASIC3 did not produce a proton-sensitive ion channel. Our observation that nmrASIC3 forms nonfunctional homomers may reflect a further adaptation of the Naked Mole-Rat to living in an environment with high-carbon dioxide levels.
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Expression of acid-sensing ion channels and selection of reference genes in mouse and Naked Mole Rat.
Molecular brain, 2016Co-Authors: Laura-nadine Schuhmacher, Ewan St John SmithAbstract:Acid-sensing ion channels (ASICs) are a family of ion channels comprised of six subunits encoded by four genes and they are expressed throughout the peripheral and central nervous systems. ASICs have been implicated in a wide range of physiological and pathophysiological processes: pain, breathing, synaptic plasticity and excitotoxicity. Unlike mice and humans, Naked Mole-Rats do not perceive acid as a noxious stimulus, even though their sensory neurons express functional ASICs, likely an adaptation to living in a hypercapnic subterranean environment. Previous studies of ASIC expression in the mammalian nervous system have often not examined all subunits, or have failed to adequately quantify expression between tissues; to date there has been no attempt to determine ASIC expression in the central nervous system of the Naked Mole-Rat. Here we perform a geNorm study to identify reliable housekeeping genes in both mouse and Naked Mole-Rat and then use quantitative real-time PCR to estimate the relative amounts of ASIC transcripts in different tissues of both species. We identify RPL13A (ribosomal protein L13A) and CANX (calnexin), and β-ACTIN and EIF4A (eukaryotic initiation factor 4a) as being the most stably expressed housekeeping genes in mouse and Naked Mole-Rat, respectively. In both species, ASIC3 was most highly expressed in dorsal root ganglia (DRG), and ASIC1a, ASIC2b and ASIC3 were more highly expressed across all brain regions compared to the other subunits. We also show that ASIC4, a proton-insensitive subunit of relatively unknown function, was highly expressed in all mouse tissues apart from DRG and hippocampus, but was by contrast the lowliest expressed ASIC in all Naked Mole-Rat tissues.
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Research data supporting “Expression of acid-sensing ion channels and selection of reference genes in mouse and Naked Mole Rat”
2016Co-Authors: Laura-nadine Schuhmacher, Ewan St John SmithAbstract:geNorm and qPCR raw data from mouse and Naked Mole-Rat samples to support the publication, Expression of acid-sensing ion channels and selection of reference genes in mouse and Naked Mole Rat
