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January 23, 2012

New Discoveries in Cell Aging

A group of researchers led by the Institute of Biotechnology and Biomedicine (IBB) and Universitat Autònoma de Barcelona (UAB) have achieved to quantify with precision the effect of protein aggregation on cell aging processes using as models the Escherichia coli bacteria and the molecule which triggers Alzheimer's disease. Scientists demonstrated that the effect can be predicted before it occurs. Protein aggregation is related to several diseases, including neurodegenerative diseases.

Journal of Molecular Biology - The Effect of Amyloidogenic Peptides on Bacterial Aging Correlates with Their Intrinsic Aggregation Propensity




The research provides an extremely reliable system with which to model and quantify the effect of protein aggregation on the viability, division and aging of cells. It also aids in further understanding the natural evolution of proteins. According to Salvador Ventura, researcher at IBB and director of the research project, "it will serve to develop computer approximations to predict the effects aggregation has on cell aging, as well as to search for molecules that act as natural chaperones, highly conserved proteins which are present also in humans and which have the ability to reduce this effect in the bacteria".

Although it is widely accepted that bad folding and aggregation of proteins reduces the cell's ability to survive and reproduce, the damage caused had not been previously measured experimentally as precisely as it was in this research.

In previous studies scientists had verified that the expression of the Alzheimer's AB42 peptide in bacteria induces the process of protein aggregation. Now they have demonstrated that this effect is coded in the protein aggregation sequence and that it depends on intrinsic properties, not on a direct response from within the cell. This makes it possible to predict the effect. Scientists also demonstrated that damage caused to the bacteria is controlled by molecular chaperones, which reduce the tendency of proteins to aggregate and favour cell survival.


The formation of aggregates by misfolded proteins is thought to be inherently toxic, affecting cell fitness. This observation has led to the suggestion that selection against protein aggregation might be a major constraint on protein evolution. The precise fitness cost associated with protein aggregation has been traditionally difficult to evaluate. Moreover, it is not known if the detrimental effect of aggregates on cell physiology is generic or depends on the specific structural features of the protein deposit. In bacteria, the accumulation of intracellular protein aggregates reduces cell reproductive ability, promoting cellular aging. Here, we exploit the cell division defects promoted by the intracellular aggregation of Alzheimer's-disease-related amyloid β peptide in bacteria to demonstrate that the fitness cost associated with protein misfolding and aggregation is connected to the protein sequence, which controls both the in vivoaggregation rates and the conformational properties of the aggregates. We also show that the deleterious impact of protein aggregation on bacterial division can be buffered by molecular chaperones, likely broadening the sequential space on which natural selection can act. Overall, the results in the present work have potential implications for the evolution of proteins and provide a robust system to experimentally model and quantify the impact of protein aggregation on cell fitness.

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