The open access paper for today takes a look at amyloid formation and some of the cellular processes that try to hold it back, processes that become increasingly disarrayed with advancing age. Amyloids are one of the distinguishing features of old tissues, absent in the tissues of younger individuals. There are a score or so of different types of amyloid, each corresponding to a particular protein that can become misfolded in a way that makes it precipitate and clump into solid aggregates between cells. Some amyloids are very well associated with specific age-related diseases, as is the case for amyloid-β and Alzheimer's disease, and as is becoming the case for transthyretin amyloid and cardiovascular disease. Others remain more obscure, and it is even possible that some do not contribute meaningfully to aging over a normal human life span.
In those cases where the biochemistry of an amyloid is well explored, as for amyloid-β, it appears that it is not the amyloid per se that is the problem, but the surrounding halo of related compounds. This environment and its interactions with cells has proven to be exceedingly complex, like most areas of interest to modern medicine. Clearing out the amyloid should nonetheless be beneficial, either by removing a source of those errant and damaging molecules, or by damping the reaction of cells to its presence, something that may also be a problem. Not all cellular reactions to the damage and change of aging are beneficial: there are plenty of examples of antagonistic pleiotropy to pick from, in which cellular behavior that helps in the context of a youthful environment is far less benign in the context of aged tissues.
Even before attaining a complete understanding of the biochemistry of any particular amyloid, a task that the Alzheimer's research community has demonstrated to be very challenging, we should be guided towards a strategy of removal. This is on the basis that amyloid is not observed in any significant amount in young tissues. The high level strategy for the development of rejuvenation therapies should be to target and revert known changes, at least in those cases where we can put forward good evidence for the change to occur due to the normal operation of metabolism. In other words that it may be a root cause of aging, not secondary to some other change. Amyloid accumulation appears a good candidate in this model, though given the complexity and still incomplete mapping of the mechanisms involved, the definitive proof will probably arrive from successful clearance rather than successful analysis.
As the population is aging, the incidence of age-related neurodegenerative diseases, such as Alzheimer and Parkinson disease, is growing. The pathology of neurodegenerative diseases is characterized by the presence of protein aggregates of disease specific proteins in the brain of patients. Under certain conditions these disease proteins can undergo structural rearrangements resulting in misfolded proteins that can lead to the formation of aggregates with a fibrillar amyloid-like structure. The role of these aggregates in disease is not fully understood: the most prevalent hypothesis is that aggregation intermediates - single or complexes of aggregation-prone proteins - are toxic to cells and that the aggregation process represents a cellular protection mechanism against these toxic intermediates.
Cells have a protein quality control (PQC) system to maintain protein homeostasis. Preserving protein homeostasis involves the coordinated action of several pathways that regulate biogenesis, stabilization, correct folding, trafficking, and degradation of proteins, with the overall goal to prevent the accumulation of misfolded proteins and to maintain the integrity of the proteome.
One of the cellular mechanisms that copes with misfolded proteins is the chaperone machinery. A molecular chaperone is defined as a protein that interacts with, stabilizes or assists another protein to gain its native and functionally active conformation without being present in the final structure. In addition to folding of misfolded proteins, molecular chaperones are also involved in a wide range of biological processes such as the folding of newly synthesized proteins, transport of proteins across membranes, macromolecular-complex assembly or protein degradation and activation of signal transduction routes. Next to their function under normal cellular conditions, chaperones play an important part during neurodegeneration when there is an overload of the PQC system by unfolded proteins. Each neurodegenerative disease is associated with a different subset of chaperones such as heat shock proteins that can positively influence the overload of unfolded proteins
Protein degradation is another key mechanism to deal with misfolded proteins. Three pathways have been described, i.e., the ubiquitin-proteasome system (UPS), chaperone mediated autophagy (CMA), and macroautophagy. Protein aggregates or proteins that escape the first two degradation pathways are directed to macroautophagy, a degradation system where substrates are segregated into autophagosomes which in turn are fused with lysosomes for degradation into amino acids. The proteins involved in neurodegenerative disease can rapidly aggregate and can thereby escape degradation when they are still soluble, the aggregates and intermediate forms are partly resistant to the known degradation pathways.
A further compensatory mechanisms involves the endoplasmic reticulum (ER). The unfolded protein response (UPR), induced during periods of cellular and ER stress, aims to reduce unfolded protein load, and restore protein homeostasis by translational repression. ER stress can be the result of numerous conditions, including amino acid deprivation, viral replication and the presence of unfolded proteins, resulting in activation of the UPR. In addition, misfolded proteins can be sequestered in distinct protein quality control compartments in the cell by chaperones and sorting factors. These compartments function as temporary storage until the protein can be refolded or degraded by the proteasome. Different compartments have been described in the literature that sequester different kind of misfolded proteins at various conditions.
Under normal conditions, the PQC can rapidly sense and correct cellular disturbances by activating stress-induced cellular responses to restore the protein balance. During aging or when stress becomes chronic, the cell is challenged to maintain proper protein homeostasis. Eventually, this can lead to chronic expression of misfolded and damaged proteins in the cell that can result in the formation of protein aggregates. The presence of aggregation-prone proteins contributes to the development of age-related diseases. The decline of protein homeostasis during aging is a complex phenomenon that involves a combination of different factors. In line with the decreased protein homeostasis, there appears to be an impairment of the upregulation of molecular chaperones during aging. Since all major classes of molecular chaperones, with the exception of the small heat shock proteins, are ATPases it has been suggested that the depletion of ATP levels during aging due to mitochondria dysfunction would affect their activity. This is reflected by the repression of ATP-dependent chaperones and the induction of ATP-independent chaperones in the aging human brain. This may contribute to the decline of chaperoning function during aging.
Under the right conditions any protein could form amyloid-like structures. Although amyloids have been traditionally related to diseases, they also have diverse functions in organisms from bacteria to human that may underlie their nature. Nevertheless, the toxicity of amyloid intermediate species associated with disease makes protein aggregation a process that has to be under tight control and regulation. In this context, aging is a key risk factor due to the progressive decline of protein homeostasis, which leads to increased protein misfolding and aggregation. This can eventually result in the onset of age-related diseases characterized by protein aggregation. As the human population becomes older, it is essential to understand the processes underlying age-related diseases that are the result of protein aggregation and its associated toxicity. This is a very broad research field, ranging from biophysics to clinical trials. Every year discoveries are made that involve the identification of factors affecting protein aggregation. It can be concluded that the overall knowledge of the aggregation process is improving, which will allow for the development of new and accurate treatments against aggregation-linked diseases.