期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 21, 期 22, 页码 -出版社
MDPI
DOI: 10.3390/ijms21228651
关键词
misfolded protein oligomers; countermeasures; kinetics; structure– toxicity relationships; membrane protection; protein homeostasis; Alzheimer’ s disease; Parkinson’ s disease
资金
- Faculty Research Fund grant from the United States Military Academy, West Point
- DTRA Service Academy Research Initiative grant [HDTRA1033862]
- Cambridge Centre for Misfolding Diseases
- Wellcome Trust [203249/Z/16/Z]
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.
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