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Kluever V, Russo B, Mandad S, Kumar NH, Alevra M, Ori A, Rizzoli SO, Urlaub H, Schneider A, Fornasiero EF. Protein lifetimes in aged brains reveal a proteostatic adaptation linking physiological aging to neurodegeneration. Sci Adv. 2022 May 20;8(20):eabn4437. PubMed.
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Emory University
In this interesting and well-conducted study, the authors measured the half-life or “lifetime” of brain proteins in mice using in-vivo metabolic labeling of amino acids and mass spectrometry. They found that in aged (21-month-old) compared to young brains (5-month-old), protein lifetimes were increased on average by 20 percent.
Interestingly, they note that many of the relatively longer-lived (rLL) proteins had key roles in neurodegenerative diseases including amyloid precursor protein (APP), sortilin-related receptor (SORL1), and the lysosomal proteolytic enzyme cathepsin D. Furthermore, the lifetime of α-synuclein was only seen increased in synaptic fractions suggesting that unique mechanisms control synuclein turnover in the synapse with age.
Alternatively, mitochondrial proteins were found to be relatively short-lived (rSL) with age, which may be associated with hypometabolic phenotypes with aging. The authors correlated protein lifetime with proteins previously identified in aggregate-rich fractions and saw a positive association with longer lived proteins being more prone to aggregate.
Another interesting finding is that the turnover for proteins with especially energetically expensive amino acid residues (e.g., cysteine, aspartate, asparagine) were significantly decreased in the aged brain. By extension, they show that, with age, rSL proteins become longer-lived and in turn rLL proteins become shorter-lived, suggesting that the brain gets “frugal” when it comes to protein synthesis over time.
Overall, these findings shed light on several mechanisms that regulate protein lifetime and stability in brain that may underlie shared defects in proteostasis observed across neurodegenerative diseases.
View all comments by Nicholas SeyfriedTechnical University of Denmark
This collaboration of German labs is a major contribution to our field. Protein-misfolding-related neurodegenerative diseases are assumed to be caused by misfolded protein aggregates, or oligomers being toxic by some direct molecular mechanism of action, e.g., seeding other proteins to misfold or disrupting cell membranes. These aggregates and oligomers have thus been targeted in trials, notably via antibodies. How this fits with the major risk factor—aging—and why it is a particular problem to neurons has been much debated, as has the lack of success of clinical strategies.
While association is not causation and the new study used mice for necessary practical reasons, the study discovered consistent quantitative proteomic associations, with thousands of data points compared, between lifetimes of disease-related proteins and aging, and biosynthetic energy costs, with more expensive proteins being more preserved during aging.
The relationships provide the strongest indication so far that the underlying disease cause may perhaps not be a specific molecular toxic mode of action per se, but rather the indirect impact these proteins have on neuronal energy budgets.
If these relationships are causal in humans, it could explain why protein misfolding becomes pathogenic specifically in neurons, some of the most energy-demanding cells, and why this happens mainly at high age. It also points to new therapies. Antibodies may be too simplistic; rather, targeting the actual turnover of the oligomers and the associated metabolic consequences may be the avenues of research moving forward.
View all comments by Kasper KeppKarolinska Institutet
Using a clever mass-spectrometry method for determining protein turnover in vivo, the authors studied the effect of aging on protein lifetimes in the brains of mice. There were plenty of good reasons for having a closer look at protein turnover in the aged brain, as there is a large body of evidence indicating that protein synthesis as well as the major systems for protein degradation—the ubiquitin-proteasome system and autophagy—are dysregulated in the aged brain. This is likely to cause changes in protein homeostasis, i.e., proteostasis, which may explain the variety of age-related neurodegenerative diseases that are marked by the accumulation of protein aggregates in affected neurons.
An intriguing finding from this study is the observation that protein lifetimes on average were increased by 20 percent in aged brains, supporting the model that major changes in proteostasis occur in brains during aging. The data became even more revealing when the authors zoomed in on the effect of specific groups of proteins. Proteins that had a relatively longer half-life in the aged brain were typically involved in stress responses, autophagy, lysosome function, and other processes linked to neurodegeneration. Relatively long-lived proteins also had a slight tendency to be more disordered, suggesting that these proteins may have an increased propensity to aggregate. Interestingly, several proteins functionally linked to amyloid protein precursor (APP) trafficking and processing were among those relatively long-lived proteins.
On the other hand, an overrepresentation of mitochondrial proteins was found in the population of relatively short-lived proteins in the aged brains. This may reflect mitochondrial dysfunction, another phenomenon linked to age-related neurodegenerative disorders.
A fascinating but somewhat puzzling observation is that there seems to be a positive correlation between the bioenergetic cost of producing a protein and its lifetime in the aged brain, as “expensive” proteins had more extended lifetimes than “cheap” proteins in the aged brains. Admittedly, it may be beneficial for cells to make optimal use of these “expensive” proteins from an energy expenditure point of view, but the molecular mechanism that would be responsible for the selective stabilization of these proteins may be harder to explain. Aged brains hanging on these proteins longer than would have been the case in younger brains may sound attractive, but may also increase the risk of old, malfunctioning proteins forming insoluble aggregates or otherwise disturbing cellular functions.
This also raises the question if an increased propensity to aggregate of these “expensive”, often large, proteins could be a cause for the more pronounced increase in their half-lives, as they may be harder to clear once aggregated. As this line of reasoning exemplifies, any attempt at explaining these data with underlying molecular mechanisms is, at this point, largely a matter of conjecture. Insights into causality and identification of confounding factors will be important, but would require additional experimentation on underlying molecular mechanisms.
This study undoubtedly provides the field with a wealth of important information that can form steppingstones for better understanding the effect of aging on proteostasis in the brain as well as its link to neurodegenerative disease, but additional mechanistic studies will be critical to learn how and why these changes in protein turnover happen. That will be the next challenge.
View all comments by Nico DantumaUniversity of Kansas
This very well-done and very interesting proteomics study provides a fundamental snapshot of how protein biology changes in the aging brain, or at least in this case in the aging mouse brain. The unbiased analysis reveals there are proteins and protein modules whose existence time increases, and proteins and protein modules whose existence time decreases. Perhaps this by itself is not surprising, but what is clearly interesting is the nature of the modules in which protein longevity increases versus decreases.
The authors broadly note two classes of long-lived proteins: (1) those that may lead to adaptive resilience under stress, and (2) those that associate for one reason or another with neurodegenerative diseases. This raises the question of whether some of the latter associate with neurodegenerative diseases because they are driving aging or disease, or are responding to aging or disease.
The data also reveal that proteins that become relatively short-lived are enriched for mitochondrial proteins. This raises the question of whether the changes in the mitochondrial proteins drive age-related changes in mitochondrial function or are driven by age-related changes in mitochondrial function. Finally, it appears that proteins with higher biosynthetic costs end up hanging around longer, which could reflect an attempt by neurons to conserve energy.
I thought the authors did a good job in considering the implications of their findings. One really can’t tell the extent to which the proteostasis changes contribute to aging, are a consequence of aging, or both. Regardless, this study leaves us with a lot to think about. We may not know the answer to these questions at this time, but I am struck by the fact that these data were generated in aging mice, that changing mitochondrial biology is a hallmark of aging, that strategic adaptations to energy stress are implicated, and the data provide links to neurodegenerative diseases. All this is arguably consistent with the view that mitochondria potentially play a relatively upstream role in an age-related disease such as AD.
View all comments by Russell SwerdlowMake a Comment
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