Biological and chemical approaches to diseases of proteostasis deficiency

Evan T. Powers, Richard I. Morimoto, Andrew Dillin, Jeffery W. Kelly, William E. Balch

Research output: Contribution to journalReview article

727 Scopus citations

Abstract

Many diseases appear to be caused by the misregulation of protein maintenance. Such diseases of protein homeostasis, or "proteostasis," include loss-of-function diseases (cystic fibrosis) and gain-of-toxic-function diseases (Alzheimer's, Parkinson's, and Huntington's disease). Proteostasis is maintained by the proteostasis network, which comprises pathways that control protein synthesis, folding, trafficking, aggregation, disaggregation, and degradation. The decreased ability of the proteostasis network to cope with inherited misfolding-prone proteins, aging, and/or metabolic/environmental stress appears to trigger or exacerbate proteostasis diseases. Herein, we review recent evidence supporting the principle that proteostasis is influenced both by an adjustable proteostasis network capacity and protein folding energetics, which together determine the balance between folding efficiency, misfolding, protein degradation, and aggregation.We review how small molecules can enhance proteostasis by binding to and stabilizing specific proteins (pharmacologic chaperones) or by increasing the proteostasis network capacity (proteostasis regulators). We propose that such therapeutic strategies, including combination therapies, represent a new approach for treating a range of diverse human maladies.

Original languageEnglish (US)
Pages (from-to)959-991
Number of pages33
JournalAnnual review of biochemistry
Volume78
DOIs
StatePublished - 2009

Keywords

  • Aging
  • Amyloid
  • Chaperones
  • Heat shock response
  • Protein folding and misfolding
  • Unfolded protein response

ASJC Scopus subject areas

  • Biochemistry

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