Amyloid Disassembly: What Can We Learn from Chaperones?

Abstract

Protein aggregation and subsequent accumulation of insoluble amyloid fibrils with cross-β structure is an intrinsic characteristic of amyloid diseases, i.e., amyloidoses. Amyloid formation involves a series of on-pathway and off-pathway protein aggregation events, leading to mature insoluble fibrils that eventually accumulate in multiple tissues. In this cascade of events, soluble oligomeric species are formed, which are among the most cytotoxic molecular entities along the amyloid cascade. The direct or indirect action of these amyloid soluble oligomers and amyloid protofibrils and fibrils in several tissues and organs lead to cell death in some cases and organ disfunction in general. There are dozens of different proteins and peptides causing multiple amyloid pathologies, chief among them Alzheimer’s, Parkinson’s, Huntington’s, and several other neurodegenerative diseases. Amyloid fibril disassembly is among the disease-modifying therapeutic strategies being pursued to overcome amyloid pathologies. The clearance of preformed amyloids and consequently the arresting of the progression of organ deterioration may increase patient survival and quality of life. In this review, we compiled from the literature many examples of chemical and biochemical agents able to disaggregate preformed amyloids, which have been classified as molecular chaperones, chemical chaperones, and pharmacological chaperones. We focused on their mode of action, chemical structure, interactions with the fibrillar structures, morphology and toxicity of the disaggregation products, and the potential use of disaggregation agents as a treatment option in amyloidosis.

Astemizole, a Second-Generation Histamine H1-Receptor Antagonist, Did Not Attenuate the Aggregation Process of α-Synuclein In Vitro

“…We found that the formation of Aβ42 fibrils was attenuated by astemizole, which was in line with a previous study that used a radioligand assay [ 15 ], but astemizole did not prevent the amyloid assembly of α-syn, even at a high molar ratio. Our results suggest that the ameliorative effects of astemizole on the formation of amyloids are rather protein-specific, while previously reported small-molecule inhibitors or chaperones can inhibit the formation of a range of amyloid proteins [ 26 , 27 ]. For example, epigallocathecin-3-gallate and several polyphenol molecules inhibit the aggregation of Aβ, α-syn, tau, human islet amyloid polypeptide, and the prion protein Sup35 [ 26 ].…”

“…For example, epigallocathecin-3-gallate and several polyphenol molecules inhibit the aggregation of Aβ, α-syn, tau, human islet amyloid polypeptide, and the prion protein Sup35 [ 26 ]. Molecular chaperones including intracellular heat-shock proteins have anti-amyloid activities on α-syn, Aβ42, tau, and SOD1 proteins [ 27 , 28 , 29 ]. The observed target-amyloid selectivity of astemizole is not unprecedented; a previous study showed that astemizole displayed different affinities for Aβ42 and tau aggregates [ 15 ], and further studies are needed to determine the reasons for the proposed selectivity of astemizole.…”

ClpL Chaperone as a Possible Component of the Disaggregase Activity of Limosilactobacillus fermentum U-21

“…Desaggregases are being intensively investigated as potential drugs targeting protein misfolding and aggregation [40,41]. Agents able to disaggregate preformed amyloids have been classified as molecular chaperones (e.g., Hsp70 and Hsp90), chemical chaperones (bile acids, steroid hormones, and trehalose) and pharmacological chaperones (amino acid derivatives, benzophenone, and tetracycline) [42]. The bacterial ATPases of the Clp proteins family have been suggested to be used for such purposes [43].…”

Cellular Protein Aggregates: Formation, Biological Effects, and Ways of Elimination

“…Catechin derivatives, non-steroidal anti-inflammatory drugs (NSAIDs), anthracycline, and tetracycline derivatives also show the ability to disassemble protein aggregate. However, they still need more research to clarify the mechanism and reveal potential risks before use in clinical treatment [100][101][102][103].…”