ISLAMABAD, Feb 24 (Online): A new study challenges the concept that protein aggregates in the brain are the direct cause of cell death in neurodegenerative diseases.
\nThe researchers noted the culprit is the body\u2019s inability to turn off the stress response in brain cells.
\nThe findings highlight the potential for using certain drugs to deactivate the brain\u2019s stress response and maintain the activity of a newly identified protein complex, SIFI.<\/p>\n
The new insights shift the focus from targeting protein aggregates to managing the stress response mechanism and introduce the potential for new treatment strategies.
\nMany neurodegenerative conditions, including Alzheimer\u2019s disease (AD) and Parkinson\u2019s 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.<\/p>\n
As a result, efforts to find treatments focused on dissolving and eliminating these protein formations have largely been unsuccessful.
\nBut now, new research published in NatureTrusted Source challenges this assumption.
\nThe 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.
\nTheir 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.<\/p>\n
Lead researcher Michael Rap\u00e9, 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. Rap\u00e9 told Medical News Today the new research highlights how \u201ca set of neurodegenerative diseases are connected through their persistent activation of a stress response pathway (the cellular stress response to mitochondrial import defects).\u201d<\/p>\n
\u201cThe stress response is normally turned off by a dedicated factor \u2014 the first example of \u2018stress response silencing\u2019 \u2014 and mutations in this factor cause early-onset dementia.\u201d
\n\u2014 Prof. Michael Rap\u00e9, lead study author<\/p>\n
How protein aggregates affect the stress response
\nNormally, cells can turn off their stress response after it\u2019s no longer needed \u201cby diverting the silencing factor (SIFI) from its stress response targets,\u201d Prof. Rap\u00e9 said.<\/p>\n
However, in these diseases, the aggregates prevent the protein complex SIFI from doing its job, which means the cell\u2019s stress response stays active when it shouldn\u2019t.<\/p>\n
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.<\/p>\n
These treatments work even without removing the aggregates.<\/p>\n
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.<\/p>\n
Keeping the stress response constantly active can harm the cells, which might be a key factor in how these diseases progress.<\/p>\n
Dr. David Merrill, PhD, board certified adult and geriatric psychiatrist and director of the Pacific Neuroscience Institute\u2019s Pacific Brain Health Center in Santa Monica, CA, not involved in this research, told MNT that this research \u201crepresents a promising new way to treat otherwise incurable neurodegenerative diseases.\u201d<\/p>\n
\u201cTurning off the stress response in cells that have otherwise lost that capability is a worthwhile approach to study,\u201d Dr. Merrill explained.<\/p>\n
Activated stress response leads to cell death
\nDiseases 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.<\/p>\n
The research also highlights that other neurodegenerative disorders, such as Mohr-Tranebj\u00e6rg syndrome, childhood ataxia, and Leigh syndrome, exhibit similar overactive stress responses and share symptoms with the early-onset dementia studied.<\/p>\n
The research team had previously believed that protein aggregates were directly lethal to neurons, perhaps by damaging internal cell structures.<\/p>\n
However, their new insights reveal that these aggregates actually block the shutdown of a stress response that cells initially activate to manage malfunctioning proteins.<\/p>\n
The perpetual activation of this stress response is what leads to cell death.<\/p>\n
The team suggests that this mechanism could also be relevant to more prevalent diseases that feature widespread protein aggregation, like Alzheimer\u2019s disease and frontotemporal dementia, although further research is necessary to explore the impact of stress signaling in these conditions.<\/p>\n
Silencing the stress response
\nNew treatment strategies could eventually involve \u201ccompounds that turn off the stress response kinase (HRI),\u201d Prof. Rap\u00e9 explained.<\/p>\n
However, the \u201cbest 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,\u201d the study author added.<\/p>\n
Further research is needed, explained Dr. Merrill. \u201cWe need robust funding and rapid development of clinical trials targeting mechanisms like the one discovered in this work,\u201d he noted.<\/p>\n
\u201cThere 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,\u201d Dr. Merrill concluded.<\/p>\n","protected":false},"excerpt":{"rendered":"
ISLAMABAD, Feb 24 (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\u2019s inability to turn off the stress response in brain cells. The […]<\/p>\n
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