| Autor: |
Kreiser RP; Department of Chemistry and Life Science, United States Military Academy, West Point, NY 10996, USA., Wright AK; Department of Chemistry and Life Science, United States Military Academy, West Point, NY 10996, USA., Block NR; Department of Chemistry and Life Science, United States Military Academy, West Point, NY 10996, USA., Hollows JE; Department of Chemistry and Life Science, United States Military Academy, West Point, NY 10996, USA., Nguyen LT; Department of Chemistry and Life Science, United States Military Academy, West Point, NY 10996, USA., LeForte K; Department of Chemistry and Life Science, United States Military Academy, West Point, NY 10996, USA., Mannini B; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK., Vendruscolo M; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK., Limbocker R; Department of Chemistry and Life Science, United States Military Academy, West Point, NY 10996, USA. |
| Abstrakt: |
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. |
