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New research suggests the body’s inability to turn off the stress response is linked to brain cell death in neurodegenerative diseases. Alpgiray Kelem/Getty Images
  • A new study challenges the concept that protein aggregates in the brain are the direct cause of cell death in neurodegenerative diseases.
  • The researchers noted the culprit is the body’s inability to turn off the stress response in brain cells.
  • The findings highlight the potential for using certain drugs to deactivate the brain’s stress response and maintain the activity of a newly identified protein complex, SIFI.
  • The new insights shift the focus from targeting protein aggregates to managing the stress response mechanism and introduce the potential for new treatment strategies.

Many neurodegenerative conditions, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), have been linked to the buildup of protein aggregates in the brain, leading researchers to believe that these protein clumps are responsible for the death of brain cells.

As a result, efforts to find treatments focused on dissolving and eliminating these protein formations have largely been unsuccessful.

But now, new research published in Nature challenges this assumption.

The study authors propose the lethal factor for brain cells is not the protein aggregates themselves but the inability of the body to deactivate the stress response in these cells and maintain the activity of a newly identified protein complex known as SIFI.

Their study demonstrates that administering a drug that can halt this stress response can rescue cells affected by a neurodegenerative condition known as early-onset dementia.

Lead researcher Michael Rapé, PhD, professor and head of the Division of Molecular Therapeutics, Dr. K. Peter Hirth Chair of Cancer Biology at UC Berkeley, said this discovery opens up potential new ways to treat neurodegenerative diseases. He explained that we find clumps of proteins, known as aggregates, inside cells in certain diseases.

Prof. Rapé told Medical News Today the new research highlights how “a set of neurodegenerative diseases are connected through their persistent activation of a stress response pathway (the cellular stress response to mitochondrial import defects).”

“The stress response is normally turned off by a dedicated factor — the first example of ‘stress response silencing’ — and mutations in this factor cause early-onset dementia.”

— Prof. Michael Rapé, lead study author

Normally, cells can turn off their stress response after it’s no longer needed “by diverting the silencing factor (SIFI) from its stress response targets,” Prof. Rapé said.

However, in these diseases, the aggregates prevent the protein complex SIFI from doing its job, which means the cell’s stress response stays active when it shouldn’t.

The research has shown that we can help cells affected by these aggregates, such as those seen in early onset dementia, by using drugs to restore the normal process of turning off the stress response.

These treatments work even without removing the aggregates.

This finding is crucial because it suggests that the real danger from these aggregates is not the aggregates themselves but how they keep the stress response running.

Keeping the stress response constantly active can harm the cells, which might be a key factor in how these diseases progress.

Dr. David Merrill, PhD, board certified adult and geriatric psychiatrist and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center in Santa Monica, CA, not involved in this research, told MNT that this research “represents a promising new way to treat otherwise incurable neurodegenerative diseases.”

“Turning off the stress response in cells that have otherwise lost that capability is a worthwhile approach to study,” Dr. Merrill explained.

Diseases that might benefit from this finding include genetic conditions leading to ataxia, which is characterized by a loss of muscle control, as well as early-onset dementia.

The research also highlights that other neurodegenerative disorders, such as Mohr-Tranebjærg syndrome, childhood ataxia, and Leigh syndrome, exhibit similar overactive stress responses and share symptoms with the early-onset dementia studied.

The research team had previously believed that protein aggregates were directly lethal to neurons, perhaps by damaging internal cell structures.

However, their new insights reveal that these aggregates actually block the shutdown of a stress response that cells initially activate to manage malfunctioning proteins.

The perpetual activation of this stress response is what leads to cell death.

The team suggests that this mechanism could also be relevant to more prevalent diseases that feature widespread protein aggregation, like Alzheimer’s disease and frontotemporal dementia, although further research is necessary to explore the impact of stress signaling in these conditions.

New treatment strategies could eventually involve “compounds that turn off the stress response kinase (HRI),” Prof. Rapé explained.

However, the “best way to treat neurodegenerative disease would be to limit aggregation and silence stress response signaling at the same time, reminiscent of combination therapy now in use in oncology,” the study author added.

Further research is needed, explained Dr. Merrill. “We need robust funding and rapid development of clinical trials targeting mechanisms like the one discovered in this work,” he noted.

“There is still much work to be done, but stress response silencing may prove to be a valuable way to slow or stop [the] progression of some neurodegenerative diseases,” Dr. Merrill concluded.