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.