ISLAMABAD, FEB 22 (ONLINE): 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 NatureTrusted Source 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
How protein aggregates affect the stress response
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.
Activated stress response leads to cell death
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.Silencing the stress response
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.
Herpes may double the risk of developing dementia
Scientists have found a link between herpes and dementia risk. istetiana/Getty Images
Anyone who has received a herpes diagnosis may be twice as likely to develop dementia than people who have not, according to a new study from Uppsala University in Sweden.
HSV-1, the type of the virus that causes cold sores or oral herpes, is most associated with the risk of dementia.
Nearly 80% of the adult population in Sweden and 57% to 80% of adults in the United States carries that type.
Anyone who has received a herpes diagnosis may be twice as likely to develop dementia than people who have not, according to a new study from Uppsala University in Sweden.
The study, which was published in the Journal of Alzheimer’s Disease, followed 1,000 70-year-old subjects for 15 years and confirmed previous research about the associations with the herpes virus and dementia.
Herpes results from infection with the herpes simplex virus (HSV), of which there are two types. Herpes simplex virus type 1 (HSV-1) causes oral herpes, affecting the mouth and surrounding skin but also potentially the genital region. Herpes simplex virus type 2 (HSV-2) typically causes genital herpes and is usually sexually transmitted. Nearly 572,000 people have HSV-2 infectionsTrusted Source each year, according to the Centers for Disease Control and Prevention (CDC).
Dementia is a wide term for cognitive decline disorders like Alzheimer’s disease and vascular dementia. It is associated with aging but is not a usual part of getting older.
Erika Vestin, a lead author of the study and a Ph.D. student at Uppsala University, told Medical News Today that the research confirms prior knowledge about the connections between dementia and herpes, but causality is still not concrete.
“We still do not have answers regarding causal mechanisms of this association, whether the virus causes the disease or if there is an indirect link,” Vestin said.
“Further, the association remains to be studied in different social and ethnic groups, and potential effects of herpes drugs on dementia risk need to be investigated in pharmaceutical drug studies,” she added.
How common is herpes and dementia?
According to the World Health Organization (WHO)Trusted Source, more than 55 million people worldwide have dementia and nearly 10 million more will receive a diagnosis of dementia each year. By 2030, it is estimated that the number of people with dementia will reach 78 million.
HSV, which remains for a person throughout their life, is quite common. According to the WHOTrusted Source, around 67% of people under age 50 globally have an HSV-1 infection, and 13% under age 50 have an HSV-2 infection., and 13% under age 50 have an HSV-2 infection. Most people with HSV-2 may not know they have it: Approximately 87.4%Trusted Source of people between the ages of 14 and 49 with genital herpes do not have a clinical diagnosis.
Up to 80% of the adult population in Sweden may have contracted HSV-1 at some point. The statistics are similar in the United States: 57% to 80% of adultsTrusted Source here have oral herpes.
The herpes virus causes sores or blisters in or around the mouth or genitals, alongside other symptoms. There is no cure for herpes, but treatment can help manage symptoms and reduce the likelihood of outbreaks recurring and transmission to partners.
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