Aggregate Proteins and Brain Aging: Interesting new findings

ResearchBlogging.orgNeurodegenerative diseases (i.e. Alzheimer's and Huntington's) often involves the formation of aggregates of proteins in a patients' brain, correlated with the process of degeneration. Some of these proteins are unique to the specific disease and others are commonly found in healthy individuals but also occur intertwined with the disease-linked types. Until now, these "common proteins" were thought to be an effect of sampling the tissues and were ignored as background. A new paper out today in PLoS Biology suggests, however, that these protein aggregates may be linked to aging. The main reason to think this is that they are found more widely (in a phyologenetic sense) than previously expected ... having been isolated in Caenorhabditis elegans, the laboratory classic roundworm model. And, in C. elegans, they seem to be linked to aging.

In neurodegenerative diseases specific proteins escape the cell's quality-control system and associate together, forming insoluble aggregates. ... we discovered that the aging process itself, in the absence of disease, leads to the insolubilization and increased aggregation propensity of several hundred proteins in the roundworm Caenorhabditis
. These aggregation-prone proteins have distinct structural and functional proprieties. We asked if this inherent age-dependent protein aggregation impacts neurodegenerative diseases. We found that proteins similar to those aggregating in old worms have also been identified as minor components of human disease aggregates. In addition, we showed that higher levels of inherent protein aggregation aggravated toxicity in a C.
elegans Huntington's disease model. Inherent protein aggregation is a new biomarker of aging. Understanding how to modulate it will lead to important insights into the mechanisms that underlie aging and protein aggregation diseases.

According to one of the study's authors, Cynthia Kenyan, "If you take people with Alzheimer's and look at their aggregates, there are many other proteins in the clump that no one has ever paid much attention to. It turns out that about half of these proteins are aggregating proteins that become insoluble as a normal part of aging."

There are several hundred proteins involved in this system, many associated with cell growth.

The paper, published in the Open Access journal PLoS Biology, is downloadable here.

David, D., Ollikainen, N., Trinidad, J., Cary, M., Burlingame, A., & Kenyon, C. (2010). Widespread Protein Aggregation as an Inherent Part of Aging in C. elegans PLoS Biology, 8 (8) DOI: 10.1371/journal.pbio.1000450

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But the important question is why does the key quality control system deteriorate?


The ultimate answer is this: Life is short, then you die.

The proximate answer is this: You die soon enough that life is short.

The phylogenetic answer is: Your ancestors had these problems so you have them too.

Interestingly, this model is one of the shortest lived organisms. They aged in the lab in a matter of days or weeks at a rate equal to years in humans, right? So it scales.

Now, we need a look at the same exact system in gobi fish and giant clams.

becca has it almost right, everything hinges the regulation of the key quality control systems (actually all of them are âkeyâ, just over different time frames).

The key regulating signaling molecule is nitric oxide. At high NO levels the quality control systems are cranked up and a greater fraction of organism resources (ATP) are devoted to quality control. At low NO levels that ATP is diverted elsewhere. As systems deteriorate, they become less efficient, they produce more ROS, and NO levels go down to compensate. This accelerates the deterioration. Then you die.