Much of the current research on neurodegenerative diseases focuses on a handful of proteins that tend to form hard clumps in the brain, including:
- beta amyloid in plaques associated with Alzheimer’s
- tau in tangles associated with Alzheimer’s
- alpha-synuclein in Lewy bodies associated with Parkinson’s and Lewy body dementia
- huntingtin associated with Huntington’s disease.
Della David, Ph.D.
Dr. Kenyon’s lab focuses on the study of aging in a microscopic roundworm called C. elegans. These roundworms are much simpler than humans or even mice. In a series of experiments using C. elegans, the researchers found there are actually hundreds of proteins that form hard clumps as roundworms age. “Our study shows that in worms, inherent protein aggregation is linked to the aging process,” says Della David, first author of the paper.
This clumping happens even when there’s no sign of disease, the researchers found. But it may not be benevolent -- protein clumping is associated with both aging and disease. As part of this study, Dr. David and her colleagues found that clumps of one of these proteins could increase the toxicity caused by clumping of another protein involved in Huntington’s disease.
This tendency of many proteins to clump with age could be one reason age is the biggest risk factor for neurodegenerative diseases. There’s a lot of work to be done before anyone can say for sure what this discovery means, though. “Our research is done in C. elegans. This is a great organism in which to perform basic research, and major discoveries relevant to humans have been made with C. elegans,” says Dr. David. “But it is too early to conclude how inherent protein aggregation would affect human aging and neurodegeneration.”
With that caution in mind, the findings do suggest new ways to look at aging and diseases like Alzheimer’s, Lewy body disease and Huntington’s. Thinking way ahead, clumps of these proteins might be used as “biomarkers,” or signs of disease and aging. “Inherent protein aggregation could be used as a new readout for how ‘healthy’ cells in an organism are,” says Dr. David. “We have not looked to see whether these proteins aggregate in humans during normal aging. However, we know that they are found in aggregates in the context of human neurodegeneration. By extrapolation, in Alzheimer’s disease we could speculate that cells that have high levels of inherent protein aggregation could be on the way to developing disease protein aggregation. So maybe the presence of these ‘common’ aggregating proteins would be an early sign of a harmful process occurring in disease.”
Thinking even further ahead, these proteins, or protein clumping in general, could be a good “target” for new treatments for neurodegenerative diseases. Dr. David is cautious about this idea. “It is unclear how inherent protein aggregation would affect disease protein aggregation and vice versa,” she says. “It is possible that inherent protein aggregation would aggravate beta amyloid or tau aggregation in Alzheimer’s, and in that case, it would be important to develop treatments to prevent this type of aggregation. But it is also possible that disease protein aggregation is the main trigger of inherent protein aggregation in humans, and therefore targeting abeta and tau would prevent inherent protein aggregation.”
The next step is to test whether protein clumping in roundworms accelerates abnormal clumping of beta amyloid, tau and alpha-synuclein, the proteins associated with Alzheimer’s and Lewy body disease, says Dr. David. On an even more basic level, “it will be important to understand the mechanisms that cause inherent protein aggregation in the absence of disease,” she says. “If we find a factor that prevents this aggregation in worms, we could evaluate whether this factor would also prevent beta amyloid or tau protein aggregation in mice.” In the meantime, scientists must also check whether these hundreds of proteins clump in humans in normal aging.
Sometimes research into Alzheimer’s and related diseases seems narrowly focused. Taking into account this type of discovery in the broader field of aging may lead to a better understanding of neurodegenerative diseases.