Therapeutic Strategies to Reduce the Toxicity of Misfolded Protein Oligomers

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...

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Bibliographic Details
Published in:International journal of molecular sciences 2020-11, Vol.21 (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: Article
Language:English
Subjects:
Aggregates
Animals
Apoptosis
Cell membranes
Cytotoxicity
Dementia
Disease
Homeostasis
Humans
Hydrogen bonds
Hydrophobicity
Intermediates
Mutation
Neurodegeneration
Neurotoxicity
Parkinson's disease
Polypeptides
Protein Aggregation, Pathological - metabolism
Protein Aggregation, Pathological - pathology
Protein Aggregation, Pathological - therapy
Protein folding
Protein interaction
Protein Multimerization
Proteins
Proteostasis Deficiencies - metabolism
Proteostasis Deficiencies - pathology
Proteostasis Deficiencies - therapy
Review
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms21228651