The Experts below are selected from a list of 324 Experts worldwide ranked by ideXlab platform
Joseph Terkel - One of the best experts on this subject based on the ideXlab platform.
-
Quantitative microscopy of Mole Rat eosinophil granule morphology
Cell and Tissue Research, 2015Co-Authors: Dina Amihai, Isaac Meilijson, Joseph Terkel, Ilan HammelAbstract:Mole Rat bone marrow cells and peritoneal eosinophils are used to study granule morphological matuRation by quantitative microscopy. The bulk eosinophil granule content is pre-stored in unique granular structures known as crystalloid or secondary granules. Mole Rat eosinophil granules exhibit the basic structure of an electron-dense crystalloid core surrounded by a lighter, homogeneous matrix. Morphometric analysis demonstRated that bone marrow-derived eosinophil sphere-like granules display a periodic, multimodal granule volume distribution. In contrast, peritoneal eosinophils display cigar-shaped granules, whose crystalloid cores are more variable in size and shape as compared to bone marrow eosinophil granules. Using a morphometric approach, we deduced that the basic granule volume quantum is similar in both cases, suggesting that the sphere-like young eosinophil granules turn into dense ellipsoidal ones by intragranular processes in which both volume and membrane surface are conserved. Crystalloid granule mediators are known to be widely associated with allergic inflammatory events, which may damage the host tissue following secretion to the extracellular environment. Based on mathematical modeling, we suggest that this deviation from sphere-like to ellipsoidal shape reflects an adaptive response of the Mole Rat to its unique solitary life.
-
SEASONAL CHANGES IN THE OVARY OF THE BLIND Mole Rat (SPALAX EHRENBERGI)
Israel Journal of Zoology, 2013Co-Authors: Uri Shanas, Ruth Shalgi, Joseph TerkelAbstract:ABSTRACT The present study is the first to examine closely the ovary of the blind Mole Rat (Spalax ehrenbergi), a solitary, highly aggressive subterranean rodent. It provides basic data on the female reproductive biology which should assist in the notoriously difficult attempts to breed this unique species. Although the Mole Rat is considered a seasonal breeder, large antral follicles were found to be present in the ovary throughout the year. Constant darkness and high tempeRatures simulating the natural burrow environment in the summer did not cause the ovary to regress. This was evident from the surprising abundance of large antral follicles, some even in the preovulatory state. Because injection of human chorionic gonadotropin (hCG) during the summer induces ovulation of these follicles, it would appear that Mole Rats are potentially able to reproduce outside of the known winter breeding season. The present work further strengthens previous assumptions (based on vaginal smears) that the Mole Rat is a r...
-
Magnetic compass orientation in the blind Mole Rat Spalax ehrenbergi
The Journal of Experimental Biology, 2001Co-Authors: Tali Kimchi, Joseph TerkelAbstract:The blind Mole Rat Spalax ehrenbergi is a solitary, subterranean rodent that digs and inhabits a system of branching tunnels, with no above-ground exits, which it never leaves unless forced to. To survive, the Mole Rat must be able to orient efficiently in its tunnel system. The sensory channels available for spatial orientation in the subterranean environment are restricted in comparison with those existing above ground. This study examined the possibility that the Mole Rat is able to perceive and use the earth9s magnetic field to orient in space. Experiments were performed using a device constructed from a pair of electromagnetic ‘Helmholtz coils’, which create a magnetic field whose direction and strength can be altered. In the first experiment, we tested a group of Mole Rats (N=33) in an eight-armed maze under the earth9s natural magnetic field to determine whether they have directional preferences for the location of their sleeping nest, food chamber and toilet site. A second group of Mole Rats (N=30) was tested for their directional preference after the earth9s magnetic field had been experimentally shifted by 180 degrees. We found that the first group exhibited a significant preference (P
-
Magnetic compass orientation in the blind Mole Rat Spalax ehrenbergi
Journal of Experimental Biology, 2001Co-Authors: Tali Kimchi, Joseph TerkelAbstract:The blind Mole Rat Spalax ehrenbergi is a solitary, subterranean rodent that digs and inhabits a system of branching tunnels, with no above-ground exits, which it never leaves unless forced to. To survive, the Mole Rat must be able to orient efficiently in its tunnel system. The sensory channels available for spatial orientation in the subterranean environment are restricted in comparison with those existing above ground. This study examined the possibility that the Mole Rat is able to perceive and use the earth's magnetic field to orient in space. Experiments were performed using a device constructed from a pair of electromagnetic ‘Helmholtz coils’, which create a magnetic field whose direction and strength can be altered. In the first experiment, we tested a group of Mole Rats (N=33) in an eight-armed maze under the earth's natural magnetic field to determine whether they have directional preferences for the location of their sleeping nest, food chamber and toilet site. A second group of Mole Rats (N=30) was tested for their directional preference after the earth's magnetic field had been experimentally shifted by 180 degrees. We found that the first group exhibited a significant preference (P<0.001) to build both their sleeping nest and their food store in the southern sector of the maze, whereas the second group shifted the location of their nests (P<0.01) and food store (P<0.05), to the northern sector of the maze, corresponding to the shift in the magnetic field. In the second experiment, we tested whether the magnetic compass orientation found in the first experiment depends on a light stimulus by testing a group of Mole Rats in the eight-armed maze under total darkness. No significant difference in directional preference between light and dark test conditions was observed. It can be concluded, therefore, that, in contrast to some amphibians and birds, magnetic compass orientation in the Mole Rat is independent of light stimulation. In the third experiment, we examined whether Mole Rats (N=24) use the earth's magnetic field as a compass cue to orient in a labyrinth. In the first stage (trials 1–13), the animals were trained to reach a goal box at the end of a complex labyrinth until all individuals had learned the task. In the second stage (trial 14), half the trained Mole Rats underwent another labyrinth trial under the earth's natural magnetic field, while the other half were tested under a magnetic field shifted by 180 degrees. We found a significant decrease (P<0.001) in performance of the Mole Rats tested under the shifted magnetic field compared with the group tested under the natural magnetic field. The findings from these experiments prove that the Mole Rat is able to perceive and use the earth's magnetic field to orient in space.
-
STRUCTURE AND FUNCTION OF ACCESSORY SEX GLANDS IN THE MALE BLIND Mole Rat (SPALAX EHRENBERGI)
Journal of Mammalogy, 2001Co-Authors: A. Gottreich, Ilan Hammel, Leah Yogev, Benjamin Bartoov, Joseph TerkelAbstract:Abstract The blind Mole Rat (Spalax ehrenbergi) is a solitary and aggressive subterranean rodent. Our study revealed the unique anatomical structure of reproductive glands, ejaculate, and spermatozoon of the male blind Mole Rat and the effect of testosterone on those glands. Unlike other rodents, only the prostate and Cowper's accessory sex glands are present, whereas coagulating gland, seminal vesicle, and preputial gland are absent. Three groups of male blind Mole Rats were examined: intact, injected, and castRated animals, and resulting differences in morphology of reproductive glands were examined histologically using quantitative measurements. Lowered testosterone levels in castRated blind Mole Rats caused a reduction in weight and star volume (υ*) of the prostate and Cowper's glands. Testosterone injection produced an increase in mass of the prostate gland but not in Cowper's glands, whereas both prostate tubuli υ* and Cowper's gland tubuli υ* also increased. The blind Mole Rat possesses only 2 acce...
Nigel C Bennett - One of the best experts on this subject based on the ideXlab platform.
-
Is the Mahali Mole-Rat (Cryptomys hottentotus mahali) a spontaneous or induced ovulator?
Canadian Journal of Zoology, 2020Co-Authors: Daniel W. Hart, Katarina Medger, B. Van Jaarsveld, Nigel C BennettAbstract:The Mahali Mole-Rat (Cryptomys hottentotus mahali (Roberts, 1913)) is a social, coopeRatively breeding subterranean rodent that breeds aseasonally. Only one female in a colony breeds and the remain...
-
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.
-
Hypofunctional TrkA Accounts for the Absence of Pain Sensitization in the African Naked Mole-Rat
Cell reports, 2016Co-Authors: Damir Omerbašić, Jane Reznick, Nigel C Bennett, Ewan St John Smith, Chris G. Faulkes, Mirko Moroni, Johanna Homfeld, Ole Eigenbrod, Matthias Selbach, Gary R. LewinAbstract:The naked Mole-Rat is a subterranean rodent lacking several pain behaviors found in humans, Rats, and mice. For example, nerve growth factor (NGF), an important mediator of pain sensitization, fails to produce thermal hyperalgesia in naked Mole-Rats. The sensitization of capsaicin-sensitive TRPV1 ion channels is necessary for NGF-induced hyperalgesia, but naked Mole-Rats have fully functional TRPV1 channels. We show that exposing isolated naked Mole-Rat nociceptors to NGF does not sensitize TRPV1. However, the naked Mole-Rat NGF receptor TrkA displays a reduced ability to engage signal transduction pathways that sensitize TRPV1. Between one- and three-amino-acid substitutions in the kinase domain of the naked Mole-Rat TrkA are sufficient to render the receptor hypofunctional, and this is associated with the absence of heat hyperalgesia. Our data suggest that evolution has selected for a TrkA variant that abolishes a robust nociceptive behavior in this species but is still compatible with species fitness.
-
Sleep in the Cape Mole Rat: A Short-Sleeping Subterranean Rodent.
Brain behavior and evolution, 2016Co-Authors: Jean-leigh Kruger, Nigel C Bennett, Nadine Gravett, Adhil Bhagwandin, Elizabeth Archer, Paul R. MangerAbstract:The Cape Mole Rat Georychus capensis is a solitary subterranean rodent found in the western and southern Cape of South Africa. This approximately 200-gram bathyergid rodent shows a nocturnal circadian rhythm, but sleep in this species is yet to be investigated. Using telemetric recordings of the electroencephalogram (EEG) and electromyogram (EMG) in conjunction with video recordings, we were able to show that the Cape Mole Rat, like all other rodents, has sleep periods composed of both rapid eye movement (REM) and slow-wave (non-REM) sleep. These Mole Rats spent on average 15.4 h awake, 7.1 h in non-REM sleep and 1.5 h in REM sleep each day. Cape Mole Rats sleep substantially less than other similarly sized terrestrial rodents but have a similar percentage of total sleep time occupied by REM sleep. In addition, the duRation of both non-REM and REM sleep episodes was markedly shorter in the Cape Mole Rat than has been observed in terrestrial rodents. Interestingly, these features (total sleep time and episode duRation) are similar to those observed in another subterranean bathyergid Mole Rat, i.e. Fukomys mechowii. Thus, there appears to be a bathyergid type of sleep amongst the rodents that may be related to their environment and the effect of this on their circadian rhythm. Investigating further species of bathyergid Mole Rats may fully define the emerging picture of sleep in these subterranean African rodents.
-
Burrow architecture and burrowing dynamics of the endangered Namaqua dune Mole Rat (Bathyergus janetta) (Rodentia: Bathyergidae)
Journal of Zoology, 2006Co-Authors: M. Herbst, Nigel C BennettAbstract:The Namaqua dune Mole Rat Bathyergus janetta is a solitary subterranean rodent that occurs in the arid and sandy regions of Namaqualand. The predictable winter rainfall and high diversity of geophytes, the predominant food resource, enables the Mole Rat to survive in this extreme environment. Burrowing and burrow system configuRation were measured by observing mound production and the excavation of six Mole Rat burrow systems. A typical burrow system comprises nest chambers, food stores, defecation sites and bolt holes, which serve as a place of retreat when the animal is alarmed or threatened. Males tend to have linear-shaped burrow systems, whereas the burrow systems of females are more reticulate. The linear nature of the male burrow system probably increases the home range used to search for potential mates. Burrow systems undergo constant excavation and re-excavation within the home range. The average burrow length ranges from 71.2 to 165 m with a mean home range of 805.8±375.5 m2.
Ewan St John Smith - One of the best experts on this subject based on the ideXlab platform.
-
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.
-
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.
-
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
-
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
-
Hypofunctional TrkA Accounts for the Absence of Pain Sensitization in the African Naked Mole-Rat
Cell reports, 2016Co-Authors: Damir Omerbašić, Jane Reznick, Nigel C Bennett, Ewan St John Smith, Chris G. Faulkes, Mirko Moroni, Johanna Homfeld, Ole Eigenbrod, Matthias Selbach, Gary R. LewinAbstract:The naked Mole-Rat is a subterranean rodent lacking several pain behaviors found in humans, Rats, and mice. For example, nerve growth factor (NGF), an important mediator of pain sensitization, fails to produce thermal hyperalgesia in naked Mole-Rats. The sensitization of capsaicin-sensitive TRPV1 ion channels is necessary for NGF-induced hyperalgesia, but naked Mole-Rats have fully functional TRPV1 channels. We show that exposing isolated naked Mole-Rat nociceptors to NGF does not sensitize TRPV1. However, the naked Mole-Rat NGF receptor TrkA displays a reduced ability to engage signal transduction pathways that sensitize TRPV1. Between one- and three-amino-acid substitutions in the kinase domain of the naked Mole-Rat TrkA are sufficient to render the receptor hypofunctional, and this is associated with the absence of heat hyperalgesia. Our data suggest that evolution has selected for a TrkA variant that abolishes a robust nociceptive behavior in this species but is still compatible with species fitness.
Andrei Seluanov - One of the best experts on this subject based on the ideXlab platform.
-
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, 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.
-
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, 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.
-
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
-
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.
-
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.
Rochelle Buffenstein - One of the best experts on this subject based on the ideXlab platform.
-
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.
-
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.
-
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.
-
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.
-
A cytosolic protein factor from the naked Mole-Rat activates proteasomes of other species and protects these from inhibition.
Biochimica et biophysica acta, 2014Co-Authors: Karl A. Rodriguez, Pawel A. Osmulski, Anson Pierce, Susan T. Weintraub, Maria Gaczynska, Rochelle BuffensteinAbstract:Abstract The naked Mole-Rat maintains robust proteostasis and high levels of proteasome-mediated proteolysis for most of its exceptional (~ 31 years) life span. Here, we report that the highly active proteasome from the naked Mole-Rat liver resists attenuation by a diverse suite of proteasome-specific small Molecule inhibitors. Moreover, mouse, human, and yeast proteasomes exposed to the proteasome-depleted, naked Mole-Rat cytosolic fractions, recapitulate the observed inhibition resistance, and mammalian proteasomes also show increased activity. Gel filtRation coupled with mass spectrometry and atomic force microscopy indicates that these traits are supported by a protein factor that resides in the cytosol. This factor interacts with the proteasome and modulates its activity. Although Heat shock protein 72 kDa (HSP72) and Heat shock protein 40 kDa (Homolog of bacterial DNAJ1) (HSP40(Hdj1)) are among the constituents of this factor, the observed phenomenon, such as increasing peptidase activity and protecting against inhibition cannot be reconciled with any known chaperone functions. This novel function may contribute to the exceptional protein homeostasis in the naked Mole-Rat and allow it to successfully defy aging.