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Measuring the Energy Barrier of the Structural Change That Initiates Amyloid Formation.

ABSTRACT: Obtaining kinetic and thermodynamic information for protein amyloid formation can yield new insight into the mechanistic details of this biomedically important process. The kinetics of the structural change that initiates the amyloid pathway, however, has been challenging to access for any amyloid protein system. Here, using the protein β-2-microglobulin (β2m) as a model, we measure the kinetics and energy barrier associated with an initial amyloidogenic structural change. Using covalent labeling and mass spectrometry, we measure the decrease in solvent accessibility of one of β2m's Trp residues, which is buried during the initial structural change, as a way to probe the kinetics of this structural change at different temperatures and under different amyloid forming conditions. Our results provide the first-ever measure of the activation barrier for a structural change that initiates the amyloid formation pathway. The results also yield new mechanistic insight into β2m's amyloidogenic structural change, especially the role of Pro32 isomerization in this reaction.

SUBMITTER: Arden BG

PROVIDER: S-EPMC7206453 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Aging is the most important risk factor for neurodegenerative diseases associated with pathological protein aggregation such as Alzheimer's disease. Although aging is an important player, it remains unknown which molecular changes are relevant for disease initiation. Recently, it has become apparent that widespread protein aggregation is a common feature of aging. Indeed, several studies demonstrate that 100s of proteins become highly insoluble with age, in the absence of obvious disease processes. Yet it remains unclear how these misfolded proteins aggregating with age affect neurodegenerative diseases. Importantly, several of these aggregation-prone proteins are found as minor components in disease-associated hallmark aggregates such as amyloid-? plaques or neurofibrillary tangles. This co-localization raises the possibility that age-dependent protein aggregation directly contributes to pathological aggregation. Here, we show for the first time that highly insoluble proteins from aged Caenorhabditis elegans or aged mouse brains, but not from young individuals, can initiate amyloid-? aggregation in vitro. We tested the seeding potential at four different ages across the adult lifespan of C. elegans. Significantly, protein aggregates formed during the early stages of aging did not act as seeds for amyloid-? aggregation. Instead, we found that changes in protein aggregation occurring during middle-age initiated amyloid-? aggregation. Mass spectrometry analysis revealed several late-aggregating proteins that were previously identified as minor components of amyloid-? plaques and neurofibrillary tangles such as 14-3-3, Ubiquitin-like modifier-activating enzyme 1 and Lamin A/C, highlighting these as strong candidates for cross-seeding. Overall, we demonstrate that widespread protein misfolding and aggregation with age could be critical for the initiation of pathogenesis, and thus should be targeted by therapeutic strategies to alleviate neurodegenerative diseases.

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Measuring the Energy Barrier of the Structural Change That Initiates Amyloid Formation.

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