Methusalem proteins in the brain

You are what you eat. During medical school, I spent a year in Lexington, Kentuck,y as an exchange student. When I went out for lunch with some of my classmates one day, the discussion came up what percentage of my total body protein would be European versus American after one year. It turns out that most proteins have a high turnover rate and are constantly rebuilt and removed. This makes sense as proteins do not have dedicated repair mechanisms as does DNA. However, some proteins seem to linger. A recent study in Cell now identifies long-lived proteins in the brain.  And it appears that the gatekeepers of the neuronal nucleus are pretty much built to last forever, and dysfunction of these proteins may contribute to neurological diseases.

The omnivore’s dilemma. In his 2006 bestselling book, Michael Pollan makes the observation that all the food consumed in the US originates in a cornfield in Iowa, either directly or indirectly. This is quite in contrast to Europe, where corn is less important and where other grains that eventually transfer proteins up into the food chain are more prominent. To find out whether a certain protein originated in Iowa or a wheat field in Northern Germany, distinctive features of amino acids can be used, such as different distributions in specific isotopes. Isotopes are variants of a specific chemical element that have a different number of neutrons. Some isotopes are radioactive and this signal can be used to determine the amount of specific isotopes in large molecules. In a laboratory setting, specific isotopes can be used label food that was consumed at a particular point in time. This methodology, called pulse-chase labeling, was used by Toyama and collaborators to determine the longevity of proteins in 6 week-old rats. The brains of the animals were analyzed at different time points; some animals were analyzed at 12 months after the initial labeling period. Using a proteomic approach, the authors sought to identify proteins that still contained traces of the initial labeling. Surprisingly, some cellular structures in neurons seemed to be long-lived.

The nuclear pore. Nuclear pore. Side view. 1. Nuclear envelope. 2. Outer ring. 3. Spokes. 4. Basket. 5. Filaments. Image is by Wikipedia reproduced under the Creative Commons Licence (http://en.wikipedia.org/wiki/File:NuclearPore_crop.svg.png)

The nuclear pore. 1. Nuclear envelope. 2. Outer ring. 3. Spokes. 4. Basket. 5. Filaments. Image is by Wikipedia reproduced under the Creative Commons Licence (http://en.wikipedia.org/wiki/File:NuclearPore_crop.svg.png)

Lasting structures. The long-lived brain proteins identified by Toyama and collaborators basically fall into two different groups, namely histones and nuclear pore proteins. Histones are the packing material for inactive DNA. Biologically, it makes sense that these proteins don’t undergo rapid replacement. They are deeply intertwined with the DNA strand, and replacing histones might lead to gene expression that disturbs the metabolism of the neuron. In eurokaryontic cells, the DNA is safely stored away in a membrane-covered nucleus.  Nuclear pore proteins assemble from several hundred proteins, and the resulting protein complex manages the transport of mRNA and proteins between the nucleus and the cytoplasm. There is no other way in or out, and every mRNA transcribed needs to pass through one these pores. Therefore, it is understandable that these cellular structures are difficult to replace. However, by keeping nuclear pores in service for too long, cells take the risk that these protein accumulate damages. And these acquired damages may contribute to aging and neurological dysfunction. Also, mutations in RANBP2, one of the nuclear pore proteins, is known to cause acute necrotizing encephalopathy, an infection-induced encephalopathy that occurs in otherwise healthy children after common infections with influenza or parainfluenza. This finding highlights the fragility of the nuclear pore system and its essential role in cellular functioning.

Summary. The study by Toyama and collaborators provides an interesting overview of what goes on in the brain with respect to protein turnover. In additional experiments, the authors also demonstrate that these long-lasting proteins persist longer in neurons than in glia and that the turnover of these essential cellular structures in the brain is much slower than in the liver. Also, gene expression of these proteins is not a good predictor for longevity. Even histone and nuclear pore genes are sometimes transcribed at relatively high levels, even though the proteins are effectively not replaced. These findings highlight that neurons acquire that specialized function such as signal transmission by giving up the possibility of replacing some of their essential structures. Their highly specialized function makes neurons so fascinating, but also vulnerable.

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