Therapeutic Strategies to Reduce the Toxicity of Misfolded Protein Oligomers

被引:30
|
作者
Kreiser, Ryan P. [1 ]
Wright, Aidan K. [1 ]
Block, Natalie R. [1 ]
Hollows, Jared E. [1 ]
Nguyen, Lam T. [1 ]
LeForte, Kathleen [1 ]
Mannini, Benedetta [2 ]
Vendruscolo, Michele [2 ]
Limbocker, Ryan [1 ]
机构
[1] US Mil Acad, Dept Chem & Life Sci, West Point, NY 10996 USA
[2] Univ Cambridge, Dept Chem, Ctr Misfolding Dis, Cambridge CB2 1EW, England
基金
英国惠康基金;
关键词
misfolded protein oligomers; countermeasures; kinetics; structure– toxicity relationships; membrane protection; protein homeostasis; Alzheimer’ s disease; Parkinson’ AMYLOID-BETA-PROTEIN; A-BETA; ALZHEIMERS-DISEASE; ALPHA-SYNUCLEIN; MOLECULAR CHAPERONES; PARKINSONS-DISEASE; METHYLENE-BLUE; IN-VITRO; NEURODEGENERATIVE DISEASES; MICROSCOPIC MECHANISMS;
D O I
10.3390/ijms21228651
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1 / 33
页数:33
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