Constant Stress Response Causes Cell Death in Neurodegenerative Disease

An unceasing stress response triggered by aggregated proteins may cause the death of brain cells in some neurodegenerative diseases, according to a paper published in the journal Nature.

“We always thought that protein clumps directly kill neurons, for example by puncturing membrane structures within these cells. Yet we now found that aggregates prevent silencing of a stress response that cells originally mount to cope with bad proteins. The stress response is always on, and that’s what kills the cells,” said study corresponding author Michael Rapé, PhD, of the University of California at Berkeley.

According to the research team, stress responses need to be turned off after a cell has cleaned up protein aggregates, or the cell will eventually die.

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In the paper, the researchers describe a large protein complex they call SIFI, which is short for “silencing factor of the integrated stress response.” SIFI cleans up aggregates and then stops the stress response triggered by the aggregated proteins.

“Aggregates kind of hijack that natural stress response-silencing mechanism, interfere with it, stall it,” Dr Rapé explained. “And so that’s why silencing never happens when you have aggregates, and that’s why cells die.”

Delivering a drug that forced the stress response to shut down effectively saved cells that mimicked early-onset dementia, the researcher team reported. About a dozen neurodegenerative diseases, including Mohr–Tranebjærg syndrome, childhood ataxia, and Leigh syndrome, are characterized by stress responses in overdrive and have symptoms similar to those of the early-onset dementia model in the study.

“We think that the same mechanisms may underlie more common pathologies that also show widespread aggregation, such as Alzheimer disease or frontotemporal dementia, but more work is needed to investigate the role of stress signaling in these diseases,” Dr Rapé said.

Researchers believe future treatment would involve medication to both turn off the stress response and to keep SIFI turned on to clean up aggregated proteins.

References

Haakonsen DL, Heider M, Ingersoll AJ, et al. Stress response silencing by an E3 ligase mutated in neurodegeneration. Nature. Published online January 31, 2024. doi:10.1038/s41586-023-06985-7

Are stressed-out brain cells the root cause of neurodegenerative disease? News release. University of California – Berkeley; February 12, 2024. Accessed February 16, 2024.