Are stressed brain cells the cause of neurodegenerative diseases?

Many neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, are characterized by the accumulation of protein clumps or aggregates in the brain, which has led scientists to speculate that protein tangles kill brain cells. brain cells. The search for treatments that can break down and remove these tangled proteins, however, has had little success.

However, a new finding from the University of California, Berkeley suggests that the buildup of aggregated proteins is not what kills brain cells. Rather, it is the body’s inability to turn off the stress response of these cells.

In a study published online January 31 in the journal NatureResearchers reported that administering a drug that forces a shutdown of the stress response rescues cells that mimic a type of neurodegenerative disease known as early-onset dementia.

According to lead researcher Michael Rapé, this discovery could offer clinicians another treatment option for some neurodegenerative diseases, at least those caused by mutations in the protein that turns off the cellular response to stress. These include hereditary diseases leading to ataxia or loss of muscle control and early dementia.

Additionally, Rapé noted that other neurodegenerative diseases, including Mohr-Tranebjærg syndrome, infantile ataxia, and Leigh syndrome, are also characterized by excessive stress reactions and have symptoms similar to those of dementia. early mimicked in the new study.

“We always thought that protein clumps directly destroy neurons, for example by perforating the membrane structures of these cells. Yet we have now discovered that the clumps prevent silencing a stress response that cells mount to origin to deal with bad proteins. The stress response is always on, and that’s what kills the cells,” said Rapé, head of the new molecular therapeutics division in UC’s Department of Molecular and Cellular Biology. Berkeley and a researcher at the Howard Hughes Medical Institute.

“We believe that the same mechanisms may underlie more common pathologies that also exhibit widespread aggregation, such as Alzheimer’s disease or frontotemporal dementia, but further work is needed to investigate the role of neurotransmitter signaling. stress in these diseases.”

Key to the findings from Rapé’s lab was the researchers’ discovery that stress responses must be turned off once a brain cell has successfully coped with a difficult situation. Rapé explained this discovery to his son in simple terms: You not only have to clean your room, but also turn off the light before going to bed. If you don’t turn off the light, you can’t fall asleep, but if you turn it off before cleaning your room, you’ll trip if you have to get up in the dark.

Likewise, a cell must clear protein aggregates before turning off the stress response. If this doesn’t turn off the stress response, the cell will eventually die.

“Aggregates don’t kill cells directly. They kill cells because they keep the lights on,” he said. “But that means you can treat these diseases, or at least the dozen neurodegenerative diseases we found, have maintained their stress responses. You treat them with an inhibitor that turns off the light. You don’t have to worry .” completely getting rid of large aggregates, changing the way we think about treating neurodegenerative diseases. And best of all, it makes it really achievable.

In their paper, Rapé and colleagues describe a very large protein complex they discovered called SIFI (SIlencing Factor of the Integrated stress response). This machine has two purposes: it cleans the aggregates and, then, deactivates the stress response triggered by the aggregated proteins.

The stress response controlled by SIFI is activated to address specific intracellular problems: the abnormal accumulation of proteins that end up in the wrong place in the cell. If components of SIFI are mutated, the cell will accumulate protein clumps and experience an active stress response. But it is the stress response that kills cells.

“The SIFI complex would normally remove aggregated proteins. When there are aggregates around, SIFI is diverted from the stress response and signaling continues. When the aggregates have been removed (the room has been cleaned before the time of bedtime), then the SIFI is no longer hijacked, and that can turn off the stress response,” he said. “Aggregates kind of hijack this natural stress response mechanism, interfere with it, block it. And that’s why silencing never happens when you have aggregates, and that’s why cells die.”

Future treatment, Rapé said, would likely involve administering a drug to turn off the stress response and a drug to keep the SIFI activated to clean up the overall mess.

Ubiquitin

Rapé, who also holds the Dr. K. Peter Hirth Chair in Cancer Biology, studies the role of ubiquitin, a ubiquitous protein in the body that targets proteins for degradation, in the regulation of normal and pathological processes in the man. In 2017, he discovered that a protein called UBR4 assembles a specific ubiquitin signal necessary for the removal of proteins that tend to aggregate inside cells.

Only later did other researchers discover that UBR4 mutations were found in certain types of inherited neurodegeneration. This discovery led Rapé to team up with colleagues at Stanford University to find out how UBR4 causes these diseases.

“It was a unique opportunity: we had an enzyme that emits an anti-aggregation signal and, when mutated, it causes aggregation disease,” he said. “You put those two things together, and you can say, ‘If you understand how this UBR4 allows sustained cell survival, that probably tells you how the aggregates kill cells.'”

They discovered that UBR4 is actually part of a much larger protein complex, which Rapé dubbed SIFI, and that this SIFI machinery was necessary when a cell could not sort proteins in its mitochondria. These proteins that end up in the wrong place in cells tend to clump together and, in turn, cause neurodegeneration.

“Surprisingly, however, we discovered that the central substrates of the SIFI complex were two proteins, one of which senses when proteins are not entering the mitochondria. This protein senses that something is wrong, then activates a kinase that s “stops most new protein synthesis as part of a stress response, giving the cell time to correct its problem by getting the proteins to the right place,” he said.

This kinase is also degraded via SIFI. A kinase is an enzyme that adds a phosphate group to another molecule, in this case a protein, to regulate important activities in the cell. By helping to degrade these two proteins, the SIFI complex deactivates the stress response caused by the accumulation of proteins clumped in the wrong place.

“This is the very first time that we have seen a stress response actively deactivated by an enzyme – SIFI – that happens to be mutated in neurodegeneration,” Rapé said.

By studying how SIFI can turn off the stress response at just the right time, only after the room has been cleaned, researchers discovered that SIFI recognizes a short protein segment that acts as a sort of zip code allowing proteins or protein precursors to to enter. in the mitochondria, where they are processed. When they are prevented from entering, they accumulate in the cytoplasm, but SIFI focuses on this zip code to eliminate them. The zip code is like the light switch.

“When aggregates accumulate in the cytoplasm, the zip code is always in the cytoplasm, and there are a lot of them,” he said.

“And it’s the same signal that you would have in the proteins that you want to turn off. So it diverts the SIFI complex from the light switch to the mess. SIFI first tries to clean up the mess, but it can’t go out.” The light. And so when you have an aggregate in the cell, the light is always on. And if the light is still on, if the stress signaling is still on, the cell will die. And that’s a problem. “

Rapé suspects that many of the intracellular protein aggregates characteristic of neurodegenerative diseases have similar consequences and could prevent the cell from turning off the stress response. If so, the fact that a drug can turn off the response and rescue brain cells bodes well for the development of treatments for potentially many neurodegenerative diseases.

Another stress response inhibitor, a drug called ISRIB discovered at UCSF in 2013, has already been shown to improve memory in mice and reduce age-related cognitive decline.

“This means that by manipulating stress reduction, by turning off the lights with chemicals, you could also target other neurodegenerative diseases,” he said. “At the very least, it’s another way we could help patients with these diseases. In the best possible way, I think it will change the way we treat neurodegenerative diseases. That’s why it’s a really important story, why I think it’s very exciting.”

Rapé, already co-founder of two startups, Nurix Therapeutics Inc. and Lyterian Therapeutics, is now seeking to develop therapies to silence the stress response while maintaining the cell’s cleanup of protein aggregates.