Mole rat: eterocefalo glabro superstar

Nel numero di giugno di TheScientist si parla dell'eterocefalo glabro, la talpa senza pelo, un animale sociale che vive in colonia in gallerie sotterranee in Africa. Ne avevo parlato in due post precedenti, per la sua resistenza ai tumori, la sua longevità, per la sua abilità ed intelligenza ad afferrare e usare oggetti per proteggersi dalla terra durante lo scavo, e per il suo genoma da poco sequenziato.

Fonte

In questo nuovo articolo, si descrive come questi animali riescano a resistere in condizioni di ipossia, quelle che ci colpiscono durante un infarto o una modificazione del circolo sanguigno cerebrale, anche 3 volte di più degli altri mammiferi. Dop o15 minuti di ipossia la talpa senza pelo non soffre di danno cerebrale, questo grazie alla presenza di canali del calcio molto selettivi, che si aprono lentamente e lasciano fluire ioni calcio gradualmente. Questi canali del calcio di tipo infantile sono presenti anche nei neonati, che sono più tollernati all'ipossia, ma vengono sostituiti durante l'infanzia da quelli di tipo adulto, più rapidi, ed il flusso di calcio risulta tossico alle cellule nervose.

L'articolo presenta la prospettiva di applicare terapie anti-infarto basate sull' induzione dell'espressione di canali del calcio di tipo neonatale:

• If a drug is designed to quickly upregulate production of infant-style channels in the brains of heart attack and stroke victims, it could provide valuable protection during a time when a steady supply of oxygen-rich blood is not reaching the brain.

Un'altra possibilità è di applicare farmaci che rallentino l'attività dei canali del calcio di tipo adulto.

Un altro aspetto meglio noto è il meccanismo alla base della resistenza ai tumori ed alle radiazioni.
In un articolo del 2013, su Nature, viene presentato un meccanismo, uno dei vari, probablimente non l'unico, che consiste nella capacità di produrre acido ialuronico ad alto peso moelcolare:
ialuronani ad alto peso molecolare e suoi recettori ad elevata affinità, sarebbero alla base di una inibizione da contatto ottimale, un controllo intercellulare, alla base della assenza di sviluppo di tumori. Una volta modificati questi polimeri o introdotto un enzima che li degrada, i tumori si sviluppano.
http://www.nature.com/nature/journal/v499/n7458/full/nature12234.html
Tian et al. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 2013, 499, 346-349. doi:10.1038/nature12234

Nella talpa senza pelo, le cellule trasformate entrano in uno stato di quiescenza, bloccano la divisione cellulare, ed eventualmente sono indotte alla morte cellulare programmata e riassorbite per autofagia.

• Moreover, subjecting mole-rats to ionizing radiation does not induce much DNA damage, as seen in other animals, nor does it result in tumors, even 5 years later. Attempts to turn naked mole-rat cells cancerous via injection of oncogenes have also failed, whereas similar methods using human, mouse, and even cattle cells results in conversion to highly aggressive and invasive cancer-forming cells. Instead of starting to proliferate in an uncontrolled manner, transformed naked mole-rat cells immediately stop dividing, though they do not die.  Several different labs have now shown that naked mole-rat cells grow to even higher densities than do mouse cells under optimal conditions, and do not avoid cellular contact under these circumstances. Rather, it has become clear that naked mole-rat tissues are better able to recognize abnormal cells, neutralize their tumorigenic properties, and repair their DNA.

Meccanismi antitumorali
la proteina antimitotica p16 è asintetizzata dal locus INK4, che nell'uomo produce due proteine chiamate secondo il loro gene p16 e p15. Ora, è stata identificata una proteina che origina da entrambi i due geni, e che nell'eterocefalo glabro svolge un ruolo attivo di inibizione della crescita tumorale.

• Scientists have identified a new protein formed by the fusion of two other proteins, which protects the rodent from cancer. The protein appears to increase when cells become crowded together, making mole rats more likely to arrest the growth of cells if they are at risk of becoming malignant. 
• Although humans lack the hybrid protein, it is produced from a cluster of genes also found in humans that makes proteins responsible for preventing damaged cells that might cause cancer from multiplying. Tests show that the protein can prevent human cells from turning cancerous.
• referred to as INK4 gene locus—synthesize the same three cancer-suppressing proteins in both species: p15^INK4b, p16^INK4a, and ARF, all of which stop cells from dividing when the cells are stressed or mutated. A student-researcher, Jorge Azpurua, wanted to clone the p16 protein of the naked mole rat for a separate experiment and noticed something unexpected: The presence of a fourth protein, which was the result of p15^INK4b and p16^INK4a being fused together.

Longevità

La talpa senza pelo vive in media 26-28 anni, con punte fino a 32 anni.  Non mostra segni di invecchiamento lento, che invece sopraggiunge rapidamente. Ad un'età corrispondente a quella umana di 92 anni, non mostrano metabolismo rallentato, artrosi, riduzione della massa muscolare. Hanno un controllo  della qualità e della degradazione delle proteine alterate molto sviluppato. Invece, sono sensibili allo stress ossidativo come tutti gli animali, anche in giovane età. Però applicano questo meccanismo del controllo delle proteine e del riparo del DNA danneggiato. E' sfatato invece che i telomeri e l'attività telomerasica differiscano, anzi questa è più bassa che in altre specie.

•  These clear indications of both attenuated and delayed physiological aging are also accompanied by the maintenance of protein quality and gene expression levels.
• Some of the oldest naked mole-rats (>26 years; equivalent to humans >105 years old) do begin to show signs of muscle loss, osteoarthritis, and cardiac dysfunction, demonstrating that mole-rats do, eventually, age like other animals. These findings of sustained good health are surprising given that the naked mole-rat is an exception to many of the current theories of why we age.
• The oxidative stress theory of aging attributes the gradual decline in function to damage caused by the free radicals or reactive oxygen species formed as an inevitable by-product of oxygen respiration. In much the same way that oxygen causes metal to rust when exposed to the elements, cell membranes, proteins, and DNA are damaged by the gas, and this accumulating damage, so goes the theory, causes physiological systems to malfunction. Naked mole-rats in captivity, however, show very high levels of oxidative damage at an early age, yet cellular function is not impaired, and the animals are able to tolerate these high levels of oxidative damage for more than 20 years.
• Another aging theory posits that the length of an organism’s telomeres, the repetitive DNA that caps the ends of chromosomes, is a biomarker of aging and will correlate with species’ life span. But compared to the much shorter-lived laboratory mouse, the naked mole-rat has relatively short telomeres—similar in length to those of humans, in fact. Alternatively, cellular levels of telomerase, a reverse transcriptase enzyme that extends telomeres, may correlate with species longevity. But while telomerase activity has been measured in mole-rat skin cells in culture, it is generally very low, and is limited to those tissues that are actively replicating, such as testes, spleen, and skin. Thus, telomere length or maintenance is unlikely to explain the exceptional longevity of the naked mole-rat.

• References

1. J. Larson, T.J. Park, “Extreme hypoxia tolerance of naked mole-rat brain,” NeuroReport, 20:1634-37, 2009. ↩
2. B.L. Peterson et al., “Adult naked mole-rat brain retains the NMDA receptor subunit GluN2D associated with hypoxia tolerance in neonatal mammals,” Neurosci Lett, 506:342-45, 2012. ↩
3. B.L. Peterson et al., “Blunted neuronal calcium response to hypoxia in naked mole-rat hippocampus,” PLoS One, 7:e31568, 2012. ↩
4. T.J. Park et al., “Selective inflammatory pain insensitivity in the African naked mole-rat (Heterocephalus glaber),” PLoS Biol, 6:e13, 2008. ↩
5. E.S. Smith et al., “The molecular basis of acid insensitivity in the African naked mole-rat,” Science, 334:1557-60, 2011. ↩
6. S. Liang et al., “Resistance to experimental tumorigenesis in cells of a long-lived mammal, the naked mole-rat (Heterocephalus glaber),” Aging Cell, 9:626-35, 2010. ↩
7. K.N. Lewis et al., “Stress resistance in the naked mole-rat: the bare essentials,” Gerontology, in press, doi:10.1159/000335966, 2012. ↩
8. E.B. Kim et al., “Genome sequencing reveals insights into physiology and longevity of the naked mole rat,” Nature, 479:223-27, 2011. ↩
9. K.A. Rodriguez et al., “Altered composition of liver proteasome assemblies contributes to enhanced proteasome activity in the exceptionally long-lived naked mole-rat,” PLoS ONE, 7:e35890, 2012. ↩
10. R. Buffenstein, “Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species,” J Comp Physiol B, 178:439-45, 2008.

Talpa senza pelo, genoma senza più segreti

Sequenziato il genoma dell'eterocefalo glabro, naked mole rat, l'animale longevo (30 anni) che resiste allo sviluppo dei tumori...
fonte
"http://www.physorg.com/news/2011-07-scientists-sequence-dna-cancer-resistant-rodent.html"

• Scientists at the University of Liverpool, in partnership with The Genome Analysis Centre, Norwich, have generated the first whole-genome sequencing data of the naked mole-rat, a rodent that is resistant to cancer and lives for more than 30 years.</p>

si attende di scoprire qualche meccanismo / pathway / antioncogene, la cui attività regoli altri modificatori attivatori / guardiani del genoma / regulatori chiave /controllori epigenetici.

Nel frattempo, ecco il sito del progetto genoma della talpa senza pelo, animale sociale ( una regina fertile, caste) capace di utilizzo di strumenti da lavoro (maschere in legno per tenere lontana la polvere)

Foto: Neil Bromhall, OSF, Getty. Dal sito

Naked Mole-Rat Genome Resource 2011.

http://naked-mole-rat.org

Aggiornamento (Biotechniques)

• the naked mole rat’s genome which contains an estimated 2.47 Gb and 22,561 genes. Comparatively, the mouse genome has 23,317 genes, and the rat genome has 22,841.

• In their analysis of cancer resistance, the researchers looked at the genes that encode the tumor-suppressor proteins p16Ink4a and p27Kip1. In humans and mice, tumor suppression is primarily mediated by p27Kip1, but previous research has proposed that p16Ink4a plays a role in the naked mole rat’s heighten tumor resistance. Although the naked mole rat’s and the mouse’s p16 gene both consist of three exons, the last exons are not very similar. Furthermore, two early stop codons in the second exon result in a significantly smaller protein. These sequence differences could affect the tumor suppressing function of these proteins.

• To study longevity, the team analyzed RNA sequencing data from the brain, kidney, and liver of newborns, young, and older naked mole rats. As a result, the researchers found that gene expression did not change significantly during the rodent’s lifespan, particularly in the brain. Specifically, the researchers found stable expression during its lifetime of the gene SMAD3, which may regulate the rate of cell death in the naked mole rat and help prevent the development of cancer.

• Aside from to SMAD3, 30 other genes had stable expression during the naked mole rat’s lifetime. For example, mitochondrial functions and telomerase reverse-transcriptase (TERT) were expressed well maintained during the organism’s lifespan.

• Likewise, the researchers found genetic modifications that could explain the naked mole rat’s pain insensitivity. Previous research had found that the rodent’s skin and cutaneous C-fibers lack neuropeptide Substance P, which is involved with pain signaling in other mammals. While the genethat encodes this peptide is intact in the naked mole rat genome, it had a deletion in the core promoter that could possibly alter its expression.

• ”Evolutionarily, pain insensitivities of animals is a novel system. It can respond to systems, it can increase survival or reproductive chance. It’s considered an evolutionary advantage, says Zhang.

• Small eyes and poor visual function in the naked mole rat were traced to two missing vertebrate opsin genes when compared with the genomes of mice, rats, and guinea pigs. However, the genes that encode the photopigments rhodopsin and melanopsin are intact in the genome, allowing the rodent to adapt to their dark environment.

“The blind mole rat cells recognized when they were over proliferating and that would induce cell death of an entire culture,” explained study author Vera Gorbunova, professor of biology and associate professor of oncology at the University of Rochester. “We started to think maybe this is how they fight cancer in vivo. That when the cells sense that they are pre-cancerous, they just trigger cell death in a very efficient way.”

To simulate cancer, Gorbunova’s lab rapidly grew primary fibroblast cells that were isolated from the rodent in culture. Her team expected to find an anticancer mechanism similar to the one that they recently described in the African naked mole rat called early contact inhibition. That mechanism prevents overcrowding in cell populations by arresting the cancerous cells with uncontrolled growth and proliferation while allowing others to survive.

Instead, Gorbunova and colleagues found that their entire culture died. “We had never seen the entire culture dish die at once before. Within three days, there were no more live cells on the plate,” said Gorbunova. 

To investigate the possible biological processes behind their observation, the researchers measured the levels of the protein interferon, which is released by an organism’s cells to initiate an immune system response to pathogens. The team found that interferon was secreted in the cells in the culture in response to the cancer stimulation. As a result, all the cells in the culture died.

The blind mole rat may have evolved this unique use of interferon to protect itself against oxygen deprivation and flooding in its natural underground tunnel habitat. So, the blind mole rats and naked mole rats seem to have evolved two different anti-cancer mechanisms to meet the survival needs of their underground environments. 

“Surprisingly, when the same scenario was repeated on different continents, evolution came to two different decisions. It just happened independently, two different solutions to the same problem,” said Gorbunova.

Now, Gorbunova plans to conduct more tests to understand how the blind mole rat’s cells actually sense hyperproliferation and how to use interferon to activate similar pathways in human cells for cancer prevention.

“I do believe that this is very applicable, and I would like to see more cancer researchers actually using those cancer resistance models because it’s a staple organism to use mice that are cancer prone," said Gorbunova. "But if we want to understand cancer resistance, mice are not very useful. It is better to look at species that are cancer resistant.”

Reference

1. Gorbunova, V., C. Hine, X. Tian, J. Ablaeva, A.V. Gudkov, E. Nevo, and A. Seluanov. 2012. Cancer resistance in the blind mole rat is mediated by concerted necrotic cell death mechanism. PNAS Early Edition. Published online October 3, 2012.
2.  Kim, E.B., X. Fang, A.A. Fushan, Z. Huang, A.V. Lobanov, L. Han, S.M. Marino, X. Sun, A.A. Turanov, et al. 2011. Genome sequencing reveals insights into physiology and longevity of the naked mole rat. Nat. [Published online October 12, 2011]
3. Edrey YH, Park TJ, Kang H, Biney A, Buffenstein R. Endocrine function and neurobiology of the longest-living rodent, the naked mole-rat Exp Gerontol 2011 Feb;46(2-3):116-123.
Proposal to Sequence an Organism of Unique Interest for Research on Aging: Heterocephalus glaber, the Naked Mole-Rat, genomics.senescence.info, 26/04/2011

eterocefalo glabro

Talpa senza pelo

Questo roditore diffuso nell'area geografica Somalia, Kenia ed Etiopia ha due interessanti proprietà.
Si tratta di un animale sociale, con funzioni precise (soldati, operai, reali) che vive in colonie di 200-300 individui, con una femmina fertile e 2-3 maschi fecondanti.
La seconda proprietà è che resiste allo sviluppo di tumori.
Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat
Articolo uscito su PNAS, del gruppo di Vera Gorbunova alla Rochester University, spiega questa proprietà con la capacità delle cellule di stabilire una inibizione da contatto, che impedisce, nelle cellule in coltura, di sovrapporsi e di muoversi, ma determina un blocco della proliferazione. Proprio questa proprietà viene meno nelle cellule tumorali.

 La talpa senza pelo riesce a vivere fino a 28 anni, ed in buona salute...

 Il secondo articolo riguarda malattie del sistema nervoso quali l'autismo e la schizofrenia.

 Premio Cozzarelli 2006, questo articolo mostra per la prima volta la correlazione tra un oncogene, che quando è attivato è coinvolto nella formazione di tumori solidi, e la sua assenza o diminuzione in malattie come l'autismo.

A genetic variant that disrupts MET transcription is associated with autism, 

si tratta di una collaborazione tra la Vanderbilt University e l'Università di Napoli, il Campo Biomedico di Roma, la Fondazione Santa Lucia, e l'IRCCS di Troina, Enna. 

Questo articolo ha fatto da apripista per i nuovi lavori su MET ed il suo coinvolgimento in altre malattie degenerative della neurocognizione.

Association of Genetic Variation in the MET Proto-Oncogene With Schizophrenia and General Cognitive Ability

Candidate Gene Studies in the GWAS Era: The MET Proto-Oncogene, Neurocognition, and Schizophrenia