Certain brain cells possess the ability to resist the toxic processes associated with Alzheimer’s disease and other forms of dementia. Scientists have now pinpointed a “protective cell cluster against harmful substances” that sustains neuronal health. The findings from this new research were published in the journal Cell.
Neurodegenerative conditions, such as dementia, are characterized by the accumulation of proteins in the brain, leading to the death of neurons. Tau proteins are among the primary culprits, although they do not always play the deciding role.
In their normal functioning capacity, these proteins help stabilize brain structures and facilitate the delivery of nutrients. However, misfolded tau proteins coalesce, and a higher degree of this clumping correlation indicates more severe neurodegenerative illness.
In a recent investigation, researchers from UCLA Health and UC San Francisco employed CRISPR-based screening to examine tau protein buildup in laboratory-grown neurons derived from human stem cells. A unique aspect distinguishes this effort.
“What gives this research particular weight is that we utilized actual human neurons carrying a disease-causing mutation,” notes study co-author Avi Samelson of UCLA Health. “These cells inherently exhibit variations in how they process the tau protein, allowing us to state with confidence that the mechanisms we identified are relevant to human disease.”
The pathogenic MAPT V337M mutation results in enhanced aggregation of tau proteins, which assume a detrimental configuration known as the “Alzheimer’s fold.”
Previously, researchers extensively scrutinized the human genome to pinpoint factors influencing disease risk, yet they often missed the underlying molecular pathways. Others described neuronal variations, but lacked the experimental foundation necessary to firmly establish causality.
“For the first time, we were able to screen human neurons for genes that dictate their resistance to the tau protein,” states study co-author Professor Martin Kampmann from the University of California, San Francisco.
Utilizing CRISPR technology, the investigators systematically evaluated “nearly every gene in the human genome.”
They suppressed or deactivated 20,000 distinct genes within human neurons in vitro to ascertain how each gene impacts the formation of toxic tau protein aggregates. In total, over 1000 genes were implicated in the buildup of brain-damaging clumps.
A subsequent screening effort revealed a crucial component—the CRL5SOCS4 protein complex—which aids brain cells in fending off the accumulation of toxic tau. CRL5SOCS4 accomplishes this by attaching a molecular tag to tau proteins, flagging them for degradation by proteasomes, the cell’s “waste disposal” structures.
To verify whether the in vitro findings corresponded with real-world observations, the researchers consulted the Seattle Alzheimer’s Disease Brain Atlas—a repository of data gathered from the brain tissues of deceased Alzheimer’s patients. This analysis revealed that brain cells with higher levels of CRL5SOCS4 expression exhibited greater resilience.
Toxic tau components can also emerge from mitochondrial impairment. As is generally known from scientific discourse, mitochondria serve as the cell’s power plants. When researchers inhibited genes impacting mitochondrial function, they induced the formation of tau fragments.
These fragments are small yet resemble a highly specific biomarker present in the blood and cerebrospinal fluid of Alzheimer’s patients. It appears that cells produce this tau fragment in reaction to oxidative stress—a type of strain arising during energy generation that intensifies with age and neurodegeneration.
Consequently, mitochondrial gene dysfunction may render the tau protein more “sticky” and prone to aggregation.
Overall, this study highlights how genetic screening methodologies can unveil previously unknown disease mechanisms. For example, the researchers uncovered several highly intriguing novel pathways governing tau protein levels, although the precise means by which they operate remains unclear.
Furthermore, clinicians need to devise ways to translate these findings into actionable treatments. The researchers proposed two distinct therapeutic avenues. The first involves boosting the activity of CRL5SOCS4, leading to more efficient clearance of tau proteins before they begin to aggregate.
One path to achieving this goal is to search for molecules that enhance the interaction between CRL5SOCS4 and the tau protein. Treatment could also target the protection of proteasomes from oxidative stress, since a stressed proteasome cannot properly process tau proteins.
As is true for various biological processes, the most effective remedies in human biology might have evolved over time through trial and error.
“Potentially, future therapies could amplify the body’s native mechanisms for preventing neurodegeneration,” surmises Kampmann.
About the Author
