A few proteins in the body are capable of misfolding or becoming otherwise altered in ways that encourage other molecules of the same protein to do the same. They can spread throughout a tissue and the body, given time, forming aggregates that precipitate into solid clumps and fibrils, surrounded by a halo of toxic biochemistry that harms cells. This is an age-related problem, likely because the systems of maintenance and recycling responsible for clearing aggregates falter with age, a victim of rising levels of molecular damage and the maladaptive reactions to that damage.
Amyloid-β, associated with Alzheimer's disease, is likely the most well studied of the amyloids, with transthyretin amyloid a close second. In the case of amyloid-β, immunotherapies have proven themselves capable of clearing this molecular waste, though without achieving patient benefits as a result. For transthyretin amyloid, existing therapies slow the aggregation process. A few other approaches that clear existing aggregates are in development but either stalled (CPHPC) or not moving forward as fast as we'd like (catabodies).
In today's open access paper, researchers discuss disaggregases as a basis for the clearance of amyloids. Disaggregases are a broad class of molecules capable of breaking apart amyloid aggregates. Some exist in the human body, well known parts of cellular stress response systems, some might be mined from other species. It is an interesting topic, and not that well explored as an approach to anti-amyloid therapies.
Cellular deregulation of amyloid formation is implicated in many neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Prion disease (PrD), and diseases affecting other parts of the body such as cataracts, Type II Diabetes, and Corneal Dystrophy (CD). Fifty different proteins or peptides involved in such amyloid aggregation disorders are structurally and functionally characterized. Typically amyloid fibrils are generated from highly amyloidogenic peptide regions of a protein as the result of protein misfolding, genetic mutations, or undesired proteolytic cleavage of that protein.
However, not all amyloid fibril formation results in detrimental diseases while some may be important to fulfil a biological function and take place in well-modulated and highly contingent condition. In some cases, functional amyloids are controlled by a balance between peptide production and clearance of amyloids, reduction in the production of oligomeric seeds, minimizing interaction of oligomeric seeds with other aggregation-prone proteins via compartmentalization and the presence of an inherent disaggregation mechanism. Understanding why certain amyloids are toxic while others are biologically important may reveal important information on the function of these amyloids or develop novel treatment avenues in amyloid associated diseases.
In order to remove toxic amyloid build-up in the cell during cellular stress, some protozoans such as yeasts are equipped with molecular machines capable of disaggregating diverse amyloid and nonamyloid structures. In yeast, several types of heat shock proteins (HSPs) are discovered to work together to form disaggregation machinery. This machinery reduces the toxic amyloid species present in the cell and restores the native function of the protein buried in the amyloids via an amyloid disaggregation process. Metazoans such as mammals might experience less cellular stress resulting in the rapid build-up of toxic amyloid in the intracellular environment but are susceptible to accumulation of both intracellular and extracellular amyloids in various pathological conditions. To disaggregate these toxic amyloids in the extracellular environment, metazoans are equipped with ATP-independent chaperones such as HtrA1 and L-PGDS instead of the ATP-dependent HSPs, found in yeast. To deal with intracellular amyloids, the metazoan cells are also equipped with other types of HSPs i.e., Hsp110, Hsp70, Hsp40, and other smaller proteins from the heat shock protein families. These diverse disaggregation mechanisms evolved to reverse the formation of the toxic amyloids and survive through cellular stress and preclude amyloid-related pathogenicity.
In neurodegenerative diseases such as Alzheimer's disease, aggregates resulting from amyloidogenic peptides deposit into senile plaques which later leads to neurofibrillary tangles, synaptic dysfunction, and neuronal cell death. In each disease, a specific peptide or protein aggregates to form amyloid fibrils. There is no effective therapeutic solution that is capable of reversing the formation of these aggregates. Amyloid disaggregation seems to be a viable option where these amyloid fibrils can be broken down into non-toxic aggregates and this would possibly help to mitigate the toxic effects caused by these amyloid fibrils. In this review, we mainly focus of the disaggregation and the remodulation of the preformed fibrils into smaller molecular weight species by different disaggregating agents instead of the inhibition of fibril formation or aggregation. Many protein disaggregases have shown promising results in in vitro studies where pathogenic amyloids fibrils are solubilized through the action of these disaggregases. These studies will be discussed in this review to showcase the potential of using amyloid disaggregation as a treatment for several neurodegenerative diseases.