TY - JOUR
T1 - Biological and chemical approaches to diseases of proteostasis deficiency
AU - Powers, Evan T.
AU - Morimoto, Richard I.
AU - Dillin, Andrew
AU - Kelly, Jeffery W.
AU - Balch, William E.
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
KW - Aging
KW - Amyloid
KW - Chaperones
KW - Heat shock response
KW - Protein folding and misfolding
KW - Unfolded protein response
UR - http://www.scopus.com/inward/record.url?scp=67650410543&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67650410543&partnerID=8YFLogxK
U2 - 10.1146/annurev.biochem.052308.114844
DO - 10.1146/annurev.biochem.052308.114844
M3 - Review article
C2 - 19298183
AN - SCOPUS:67650410543
SN - 0066-4154
VL - 78
SP - 959
EP - 991
JO - Annual review of biochemistry
JF - Annual review of biochemistry
ER -