A number of different proteins can misfold or otherwise be altered in ways that cause them to precipitate into solid deposits. The best known of these are best known because they are are a contributing cause of age-related disease, through their disruption of normal tissue function or via a surrounding halo of biochemistry that is in some way toxic to cells. There are twenty or so forms of amyloid deposits, for example, and of these the most attention is given to the amyloid-β involved in Alzheimer’s disease – though transthyretin amyloid is catching up, given the growing evidence for its role in heart failure. In the paper here, the authors suggest that the way in which amyloids and other similar deposits get started involves interactions between the aggregation of potentially many other proteins: in other words that proteins A and B might aggregate without any great evidence for a link to resulting harm, but their aggregation acts to seed the aggregation of protein C that is very definitely harmful to health over the years.
A variety of neurodegenerative diseases are associated with the misfolding and aggregation of specific proteins. In Alzheimer’s disease (AD), amyloid-β (Aβ) peptides and tau proteins aggregate and ultimately form the characteristic pathological hallmarks: amyloid plaques and neurofibrillary tangles (NTFs) respectively. In recent years, understanding the initiation and spread of these hallmark protein aggregates has become a central area of investigation. The current model stipulates that aggregation in disease is initiated by a protein seed that forms a template for further protein aggregation. Support for this model comes from research showing that the exogenous addition of minute amounts of Aβ or tau seeds greatly accelerates the onset of aggregation both in vitro and in vivo. An important and currently understudied question is how aging influences protein aggregation in neurodegeneration. Recently, physiological protein insolubility in the context of aging has become a hot topic of research. Indeed, numerous publications demonstrate that protein aggregation is not restricted to disease but a normal consequence and possibly cause of aging.
Until now, it remains unclear whether and how age-dependent protein aggregation and disease-associated protein aggregation influence each other. One possibility is that age-dependent aggregates indirectly accelerate disease-associated protein aggregation by stressing the cell and/or titrating away anti-aggregation factors. Another possibility is a direct interaction whereby disease-associated proteins and age-dependent aggregation-prone proteins co-aggregate. In support of this latter hypothesis, proteins prone to aggregate during normal aging are significantly overrepresented as minor protein components in amyloid plaques and NFTs. Recent research reveals that the sequestration of these age-dependent aggregation-prone proteins in the disease aggregates is a source of toxicity. However, whether misfolded proteins aggregating with age can form heterologous seeds that initiate Aβ aggregation has not been investigated.
Although current research focuses on homologous seeding, there are a few examples of cross-seeding (or heterologous seeding) mostly between different disease-aggregating proteins. For instance, Aβ is a potent seed for the aggregation of human islet amyloid polypeptide (hIAPP) involved in type II diabetes; Aβ and prion protein PrPSc cross-seed each other and accelerate neuropathology; and both α-synuclein and Aβ co-aggregate with tau and enhance tau pathology in vivo. Finally, we recently showed that cross-seeding between different age-dependent aggregating proteins is possible in the absence of disease. Here, we demonstrate that cross-seeding during aging is likely to be an important mechanism underlying protein aggregation in AD.
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-β 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-β aggregation. Instead, we found that changes in protein aggregation occurring during middle-age initiated amyloid-β aggregation. Mass spectrometry analysis revealed several late-aggregating proteins that were previously identified as minor components of amyloid-β 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.