Kinetic analysis reveals the diversity of microscopic mechanisms through which molecular chaperones suppress amyloid formation

Abstract

It is increasingly recognized that molecular chaperones play a key role in modulating the formation of amyloid fibrils, a process associated with a wide range of human disorders. Understanding the detailed mechanisms by which they perform this function, however, has been challenging because of the great complexity of the protein aggregation process itself. In this work, we build on a previous kinetic approach and develop a model that considers pairwise interactions between molecular chaperones and different protein species to identify the protein components targeted by the chaperones and the corresponding microscopic reaction steps that are inhibited. We show that these interactions conserve the topology of the unperturbed reaction network but modify the connectivity weights between the different microscopic steps. Moreover, by analysing several protein-molecular chaperone systems, we reveal the striking diversity in the microscopic mechanisms by which molecular chaperones act to suppress amyloid formation.

Update on Alzheimer's Disease Therapy and Prevention Strategies

“…In recent years, increasing evidence suggests that molecular chaperones might modulate the aggregation of amyloid proteins and therefore play a key protective role in neurodegenerative diseases characterized by protein misfolding. This hypothesis relies on the observation, supported by in vitro and animal studies, that several chaperones and chaperone-like proteins, including the extracellular chaperone clusterin and several heat shock proteins (HSP70, HSP90, and DNAJ) (40)(41)(42)(43)(44)(45)(46), share the ability to decrease significantly pathological aggregation of proteins such as Aβ (44), islet amyloid polypeptide (IAPP) (45), the yeast prion protein Ure2p (46), and the polyglutamine peptide (47).…”

“…Importantly, each chaperone seems to interfere with amyloid aggregation through a different mechanism, and the efficiency of the aggregation inhibition appears to be a function of the specific aggregation phase that the chaperone affects (44). Indeed, the aggregation of amyloid proteins results from a variety of microscopic chemical events, such as primary nucleation, fibril elongation, fibril fragmentation, and secondary nucleation (48).…”

“…The nonlinearity of this process (49) generates a heterogeneous population of protein species ranging from monomers to oligomers and from protofibrils to long fibrils, and each of these species represents a possible chaperone target. According to the kinetic model recently presented by Arosio et al (44), the effect of the chaperone changes the relative contribution of each microscopic event and changes the overall rate of aggregation. This model allows analysis of changes in kinetic rates in order to understand the microscopic events affected by the chaperone and therefore make predictions about the aggregate species that should be targeted.…”

“…For example, chaperones that preferentially inhibit primary nucleation bind intermediate aggregates rather than monomers (e.g., DNAJB6-mediated inhibition of Aβ 42 ), whereas proteins that selectively affect secondary nucleation affect the catalytic activity of the fibril surface (e.g., the molecular chaperone domain BRICHOS-induced effect on Aβ 42 aggregation). Some chaperones and chaperone-like proteins can interfere with more than one microscopic event, achieving a more potent inhibition of aggregation (e.g., αB-crystallin and Bri2 BRICHOS affect both elongation and secondary nucleation of Aβ 42 ) (44).…”

The Amyloid Phenomenon and Its Links with Human Disease

“…Living systems have a host of processes by which protein homeostasis is maintained (including molecular chaperones, quality-control systems, and degradation mechanisms) that we now know can act very specifically on different microscopic steps in the aggregation process of given proteins. Thus, for example, some chaperones target soluble misfolded proteins for degradation while others, however, interact with such species and inhibit their involvement in the initial primary nucleation process (Cohen et al 2015;Wright et al 2015;Arosio et al 2016). Both such mechanisms, if completely effective, could prevent the aggregation of misfolded proteins completely unless, of course, preformed aggregates are introduced from external sources, as in the prion disorders.…”