Therapeutic Strategies to Reduce the Toxicity of Misfolded Protein Oligomers

• Published in: International journal of molecular sciences Vol. 21; no. 22; p. 8651
• Main Authors: Kreiser, Ryan P, Wright, Aidan K, Block, Natalie R, Hollows, Jared E, Nguyen, Lam T, LeForte, Kathleen, Mannini, Benedetta, Vendruscolo, Michele, Limbocker, Ryan
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 17.11.2020; MDPI
• Subjects: Aggregates; Animals; Apoptosis; Cell membranes; countermeasures; Cytotoxicity; Dementia; Disease; Homeostasis; Humans; Hydrogen bonds; Hydrophobicity; Intermediates; kinetics; membrane protection; misfolded protein oligomers; Mutation; Neurodegeneration; Neurotoxicity; Parkinson's disease; Pathogenesis; Polypeptides; Protein Aggregation, Pathological - metabolism; Protein Aggregation, Pathological - pathology; Protein Aggregation, Pathological - therapy; Protein folding; protein homeostasis; Protein interaction; Protein Multimerization; Proteins; Proteostasis Deficiencies - metabolism; Proteostasis Deficiencies - pathology; Proteostasis Deficiencies - therapy; Review; structure–toxicity relationships; Alzheimer’s disease; countermeasures; protein homeostasis; membrane protection; misfolded protein oligomers; structure–toxicity relationships; kinetics; Parkinson’s disease
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21228651

The aberrant aggregation of proteins is implicated in the onset and pathogenesis of a wide range of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Mounting evidence indicates that misfolded protein oligomers produced as intermediates in the aggregation process are potent neurotoxic agents in these diseases. Because of the transient and heterogeneous nature of these elusive aggregates, however, it has proven challenging to develop therapeutics that can effectively target them. Here, we review approaches aimed at reducing oligomer toxicity, including (1) modulating the oligomer populations (e.g., by altering the kinetics of aggregation by inhibiting, enhancing, or redirecting the process), (2) modulating the oligomer properties (e.g., through the size-hydrophobicity-toxicity relationship), (3) modulating the oligomer interactions (e.g., by protecting cell membranes by displacing oligomers), and (4) reducing oligomer toxicity by potentiating the protein homeostasis system. We analyze examples of these complementary approaches, which may lead to the development of compounds capable of preventing or treating neurodegenerative disorders associated with protein aggregation.