UT Southwestern Medical Center researchers have announced findings that link blindness in animal models to a brain-wide cellular stress response that’s a common risk factor for dementia.
Their findings were published in Nature Communications in late 2024—and could help explain the connection between vision or hearing loss and dementia. The research was funded by grants from the National Institutes of Health.
“Our study provides mechanistic insight into how sensory impairment could be a potential risk factor for dementia and also emphasizes the importance of restoring or maintaining sensory systems to minimize complications,” Helmut Krämer, Ph.D., professor of neuroscience and cell biology at UT Southwestern, said in a statement.
Krämer co-led the study with Katherine Wert, Ph.D., assistant professor of ophthalmology and molecular biology, and Shashank Shekhar, Ph.D., a postdoctoral fellow in the Krämer Lab.
UTSW said that over the past decade, researchers have discovered that people with vision or hearing loss are significantly more likely to develop dementia.
The university said that studies have estimated that hearing loss in midlife contributes to 8.2% of dementia cases worldwide, and vision impairment is associated with 1.8% of U.S. dementia cases.
The biological mechanism behind this link hasn’t been known, UTSW said.
Long-term damage from integrated stress response
Helmut Krämer, Ph.D., professor of neuroscience and cell biology at UT Southwestern and a member of the Peter O’Donnell Jr. Brain Institute.
The university said that while studying molecular signaling in fruit flies, Krämer and Shekhar and their colleagues made an accidental discovery: The brains of fruit flies genetically altered to be blind had a widespread integrated stress response, or ISR.
Krämer said that ISR protects cells in the body from conditions including starvation, viral infection, and oxygen deprivation by restricting cells’ protein production and turning on genes that fix cellular damage. Should ISR remain in effect for extended periods, it can kill cells through apoptosis — a mechanism to eliminate damaged cells that are unlikely to recover and threaten neighboring cells, Krämer said.
Consequently, ISR is associated with neurodegenerative disorders, including Alzheimer’s disease and other forms of dementia, UTSW said.
Researchers said they saw ISR-propagating proteins known as ATF4 and XRP1 throughout the brains of the blind flies, but that they were in an unlikely place.
Instead of being in the nucleus of affected cells, where they typically influence genes involved in ISR, ATF4 and XRP1 were found in molecular condensates, UTSW said. These droplets within a cell remain separate from its other contents, much like oil in water.
Different species, similar results
Katherine Wert, Ph.D., assistant professor of ophthalmology and molecular biology at UT Southwestern and a member of the Peter O’Donnell Jr. Brain Institute.
UTSW said that when researchers in the Wert Lab looked at the brains of mice carrying genetic mutations that induced blindness, they saw a similar phenomenon.
They said that the condensates bore a close resemblance to stress granules, a similar droplet that forms inside nerve cells under stress. UTSW said that when the researchers used a drug known to dissolve these stress granules, it also dissolved the condensates that bound ATF4 and XRP1, suggesting the condensates and stress granules might share a common purpose.
Krämer said that it’s still unclear how such condensates might spur dementia if they develop in the brains of patients with blindness or other sensory impairments.
One idea, Krämer said, is that preventing proteins that propagate ISR from entering the cell nucleus might initially be protective, preventing long-term ISR that could cause apoptosis. The condensates could, however, restrict ISR-associated proteins from responding to other neural complications, such as the overproduction of proteins associated with Alzheimer’s disease, making cells more vulnerable to damage, Krämer said.
Wert said that future studies will assess whether dissolving the molecular condensates could have a positive or negative effect on neurodegeneration.
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