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Nat Rev Drug Discov. 2015 Nov;14(11):759-80. doi: 10.1038/nrd4593. Epub 2015 Sep 4.

Targeting protein aggregation for the treatment of degenerative diseases.

Author information

1
Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA.
2
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
3
Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037, USA.
4
Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, California 92037, USA.
5
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
6
The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.

Abstract

The aggregation of specific proteins is hypothesized to underlie several degenerative diseases, which are collectively known as amyloid disorders. However, the mechanistic connection between the process of protein aggregation and tissue degeneration is not yet fully understood. Here, we review current and emerging strategies to ameliorate aggregation-associated degenerative disorders, with a focus on disease-modifying strategies that prevent the formation of and/or eliminate protein aggregates. Persuasive pharmacological and genetic evidence now supports protein aggregation as the cause of postmitotic tissue dysfunction or loss. However, a more detailed understanding of the factors that trigger and sustain aggregate formation and of the structure-activity relationships underlying proteotoxicity is needed to develop future disease-modifying therapies.

PMID:
26338154
PMCID:
PMC4628595
DOI:
10.1038/nrd4593
[Indexed for MEDLINE]
Free PMC Article

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