Biological and chemical approaches to diseases of proteostasis deficiency

Annu Rev Biochem. 2009;78:959-91. doi: 10.1146/annurev.biochem.052308.114844.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Brain Diseases / metabolism
  • Cystic Fibrosis / metabolism
  • Humans
  • Molecular Chaperones / metabolism
  • Protein Conformation
  • Protein Folding*
  • Protein Stability
  • Proteins / chemistry*
  • Proteins / metabolism*

Substances

  • Molecular Chaperones
  • Proteins