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A groundbreaking study led by researchers at the University of California, Berkeley, has challenged conventional wisdom about the underlying causes of neurodegenerative diseases like Alzheimer’s and Parkinson’s. Contrary to previous assumptions, the accumulation of protein aggregates in the brain may not be what directly kills brain cells. Instead, it’s the failure of the body to switch off the stress response that proves fatal.
Published in the journal Nature, the study sheds new light on the intricate mechanisms involved in neurodegenerative diseases. Lead researcher Michael Rapé, head of the Division of Molecular Therapeutics at UC Berkeley, explained that their findings could revolutionize the approach to treating these debilitating conditions.
“We always thought that protein clumps directly kill neurons, but we now found that aggregates prevent the silencing of a stress response that cells mount to cope with bad proteins,” said Rapé. “The stress response is always on, and that’s what kills the cells.”
The research focused on a specific type of protein aggregation associated with neurodegenerative diseases, particularly early-onset dementia. By delivering a drug that shuts down the stress response, the researchers were able to rescue brain cells in laboratory experiments mimicking this type of dementia.
“We think that the same mechanisms may underlie more common pathologies, such as Alzheimer’s disease or frontotemporal dementia,” Rapé added.
Central to the discoveries made by Rapé’s team is the identification of a protein complex called SIFI (SIlencing Factor of the Integrated stress response). This complex serves a dual function: clearing up protein aggregates and turning off the stress response triggered by these aggregates.
“The SIFI complex clears out the aggregating proteins and then turns off the stress response,” explained Rapé. “When aggregates are present, SIFI is diverted from silencing the stress response, leading to cell death.”
The study’s findings suggest a promising avenue for potential treatments. By administering drugs that turn off the stress response and keep SIFI activated, it may be possible to rescue brain cells affected by neurodegenerative diseases.
Already, stress response inhibitors like the drug ISRIB have shown promise in improving memory and reducing cognitive decline in animal models.
“We could potentially target other neurodegenerative diseases by manipulating stress silencing,” Rapé said. “This study has the potential to change how we treat these diseases, offering hope for patients and paving the way for innovative therapies.”
The research, supported by the Stinehart-Reed Foundation and the National Institutes of Health, represents a significant step forward in understanding and potentially treating neurodegenerative diseases. Rapé and his team are now focused on developing therapies based on their groundbreaking discoveries, aiming to bring relief to patients affected by these devastating conditions.
