Posts Tagged ‘cell death’


Jan Carette and his colleagues have discovered a “death code” that unleashes a type of cell death.

Dying cells generally have two options: go quietly, or go out with a bang.

The latter, while more conspicuous, is also mechanistically more mysterious. Now, scientists at the Stanford University School of Medicine have pinpointed what they believe is the molecular “code” that unleashes this more violent variety of cell death.

This particular version of cell suicide is called necroptosis, and it typically occurs as a result of some sort of infection or pathogenic invader. “Necroptosis is sort of like the cell’s version of ‘taking one for the team,’” said Jan Carette, PhD, assistant professor of microbiology and immunology. “As the cell dies, it releases its contents, including a damage signal that lets other cells know there’s a problem.”

Seen in this light, necroptosis seems almost altruistic, but the process is also a key contributor to autoimmune diseases; it’s even been implicated in the spread of cancer.

In a new study, Carette and his collaborators discovered the final step of necroptosis, the linchpin upon which the entire process depends. They call it “the death code.”

Their work, which was published online June 7 in Molecular Cell, not only clears up what happens during this type of cell death, but also opens the door to potential new treatments for diseases in which necroptosis plays a key role, such as inflammatory bowel disease and multiple sclerosis. Carette is the senior author, and postdoctoral scholar Cole Dovey, PhD, is the lead author.

Initiating detonation

When a cell’s health is threatened by an invader, such as a virus, a cascade of molecular switches and triggers readies the cell for death by necroptosis. Until recently, scientists thought they had traced the pathway down to the last step. But it turns out that the entire chain is rendered futile without one special molecule, called inositol hexakisphosphate, or IP6, which is part of a larger collection of molecules known as inositol phosphates. Carette likens IP6 to an access code; only in this case, when the code is punched in, it’s not a safe or a cellphone that’s unlocked: It’s cell death. Specifically, a protein called MLKL, which Carette has nicknamed “the executioner protein,” is unlocked.

“This was a big surprise. We didn’t know that the killer protein required a code, and now we find that it does,” Dovey said. “It’s held in check by a code, and it’s released by a code. So only when the code is correct does the killer activate, puncturing holes in the cell’s membrane as it prepares to burst the cell open.”

MLKL resides inside the cell, which may seem like an error on evolution’s part; why plant an explosive in life’s inner sanctum? But MLKL is tightly regulated, and it requires multiple green lights before it’s cleared to pulverize. Even if all other proteins and signaling molecules prepare MLKL for destruction, IP6 has the final say. If IP6 doesn’t bind, MLKL remains harmless, like a cotton ball floating inside the cell.

When it’s not killing cells, MLKL exists as multiple units, separate from one another. But when IP6 binds to one of these units, the protein gathers itself up into one functional complex. Only then, as a whole, is MLKL a full-fledged killer. It’s like a grenade split into its component parts. None of them are functional on their own. But put back together, the tiny bomb is ready to inflict damage.

“We’ve come to realize that, after the cell explodes, there are these ‘alarm’ molecules that alert the immune system,” Dovey said. “When the cell releases its contents, other cells pick up on these cautionary molecules and can either shore up defenses or prepare for necroptosis themselves.”

Screening for the Grim Reaper

In their quest to understand exactly how necroptosis occurs, Carette and Dovey performed an unbiased genetic screen, in which they scoured the entire genome for genes that seemed to be particularly critical toward the end of the pathway, where they knew MLKL took action. Before the IP6 finding, it was known that an intricate pathway impinged on MLKL. But only through this special genetic screen, in which they systematically tested the function of every gene at this end stage, were they able to see that IP6 was the key to necroptosis.

“Genetic screens are a lot of fun because you never know what you’re going to get,” Carette said. “We feel quite excited that we’ve been able to pinpoint IP6.”

Their screen revealed that IP6 binds with especially high specificity. Other similar versions of inositol phosphate, such as IP3, didn’t pass muster, and when bound to MLKL had no effect. This gave Carette an interesting idea. For conditions like irritable bowel disease, in which erroneous necroptosis contributes to the severity of the disease, it would be desirable to disable IP6 from binding under those conditions. Perhaps blocking the binding site, or tricking MLKL into binding to one of the other versions of inositol phosphate, could do the trick. Either way, Carette and his collaborators are now digging further into the structure of IP6 bound to MLKL to better understand exactly how the killer is unleashed.

“In terms of drug discovery, inositol phosphates have been somewhat ignored, so we’re really excited to be able to look into these small molecules for potential therapeutic reasons,” Carette said.

https://www.technologynetworks.com/cell-science/news/cellular-death-code-identified-304850?utm_campaign=Newsletter_TN_BreakingScienceNews&utm_source=hs_email&utm_medium=email&utm_content=63609833&_hsenc=p2ANqtz-9qdyzMcEm3q0J6mlEARWf6NhG5b_3NFqLfwxNaoJ8n6Y4bATQcn5d8BjpMNJZ4EFWXploBzGufQZD5OhVtNnjSDPtCtQ&_hsmi=63609833

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Infection with the common parasite Toxoplasma gondii promotes accumulation of a neurotransmitter in the brain called glutamate, triggering neurodegenerative diseases in individuals predisposed to such conditions.

Written by Honor Whiteman

This is the finding of a new study conducted by researchers from the University of California-Riverside (UC-Riverside), recently published in PLOS Pathogens.

T. gondii is a single-celled parasite that can cause a disease known as toxoplasmosis.

Infection with the parasite most commonly occurs through eating undercooked, contaminated meat or drinking contaminated water.

It may also occur through accidentally swallowing the parasite after coming into contact with cat feces – by cleaning a litter tray, for example.

Though more than 60 million people in the United States are believed to be infected with T. gondii, few people become ill from it; a healthy immune system can normally stave it off.

As such, most people who become infected with the parasite are unaware of it.

Those who do become ill from T. gondii infection may experience flu-like symptoms – such as swollen lymph glands or muscle aches – that last for at least a month.

In severe cases, toxoplasmosis can cause damage to the eyes, brain, and other organs, though such complications usually only arise in people with weakened immune systems.

The new study, however, suggests there may be another dark side to T. gondii infection: it may lead to development of neurodegenerative disease in people who are predisposed to it.

To reach their findings, lead author Emma Wilson – an associate professor in the Division of Biomedical Sciences at the UC-Riverside School of Medicine – and colleagues focused on how T. gondii infection in mice affects glutamate production

How a build-up of glutamate can damage the brain

Glutamate is an amino acid released by nerve cells, or neurons. It is one of the brain’s most abundant excitatory neurotransmitters, aiding communication between neurons.

However, previous studies have shown that too much glutamate may cause harm; a build-up of glutamate is often found in individuals with traumatic brain injury (TBI) and people with certain neurodegenerative diseases, such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS).

The researchers explain that excess glutamate accumulates outside of neurons, and this build-up is regulated by astrocytes – cells in the central nervous system (CNS).

Astrocytes use a glutamate transporter called GLT-1 in an attempt to remove excess glutamate from outside of neurons and convert it into a less harmful substance called glutamine, which cells use for energy.

“When a neuron fires, it releases glutamate into the space between itself and a nearby neuron,” explains Wilson. “The nearby neuron detects this glutamate, which triggers a firing of the neuron. If the glutamate isn’t cleared by GLT-1 then the neurons can’t fire properly the next time and they start to die.”


T. gondii increases glutamate by inhibiting GLT-1

n mice infected with T. gondii, the researchers identified an increase in glutamate levels.

They found that the parasite causes astrocytes to swell, which impairs their ability to regulate glutamate accumulation outside of neurons.

Furthermore, the parasite prevents GLT-1 from being properly expressed, which causes an accumulation of glutamate and misfiring of neurons. This may lead to neuronal death, and ultimately, neurodegenerative disease.

“These results suggest that in contrast to assuming chronic Toxoplasma infection as quiescent and benign, we should be aware of the potential risk to normal neurological pathways and changes in brain chemistry.” – Emma Wilson

Next, the researchers gave the infected mice an antibiotic called ceftriaxone, which has shown benefits in mouse models of ALS and a variety of CNS injuries.

They found the antibiotic increased expression of GLT-1, which led to a reduction in glutamate build-up and restored neuronal function.

Wilson says their study represents the first time that T. gondii has been shown to directly disrupt a key neurotransmitter in the brain.

“More direct and mechanistic research needs to be performed to understand the realities of this very common pathogen,” she adds.

While their findings indicate a link between T. gondii infection and neurodegenerative disease, Wilson says they should not be cause for panic.

“We have been living with this parasite for a long time,” she says. “It does not want to kill its host and lose its home. The best way to prevent infection is to cook your meat and wash your hands and vegetables. And if you are pregnant, don’t change the cat litter.”

The team now plans to further investigate what causes the reduced expression of GLT-1 in T. gondii infection.

http://www.medicalnewstoday.com/articles/310865.php