TY - JOUR
T1 - Progressive disruption of cellular protein folding in models of polyglutamine diseases
AU - Gidalevitz, Tali
AU - Ben-Zvi, Anat
AU - Ho, Kim H.
AU - Brignull, Heather R.
AU - Morimoto, Richard I.
PY - 2006/3/10
Y1 - 2006/3/10
N2 - Numerous human diseases are associated with the chronic expression of misfolded and aggregation-prone proteins. The expansion of polyglutamine residues in unrelated proteins is associated with the early onset of neurodegenerative disease. To understand how the presence of misfolded proteins leads to cellular dysfunction, we employed Caenorhabditis elegans polyglutamine aggregation models. Here, we find that polyglutamine expansions disrupted the global balance of protein folding quality control, resulting in the loss of function of diverse metastable proteins with destabilizing temperature-sensitive mutations. In turn, these proteins, although innocuous under normal physiological conditions, enhanced the aggregation of polyglutamine proteins. Thus, weak folding mutations throughout the genome can function as modifiers of polyglutamine phenotypes and toxicity.
AB - Numerous human diseases are associated with the chronic expression of misfolded and aggregation-prone proteins. The expansion of polyglutamine residues in unrelated proteins is associated with the early onset of neurodegenerative disease. To understand how the presence of misfolded proteins leads to cellular dysfunction, we employed Caenorhabditis elegans polyglutamine aggregation models. Here, we find that polyglutamine expansions disrupted the global balance of protein folding quality control, resulting in the loss of function of diverse metastable proteins with destabilizing temperature-sensitive mutations. In turn, these proteins, although innocuous under normal physiological conditions, enhanced the aggregation of polyglutamine proteins. Thus, weak folding mutations throughout the genome can function as modifiers of polyglutamine phenotypes and toxicity.
UR - http://www.scopus.com/inward/record.url?scp=33644850056&partnerID=8YFLogxK
U2 - 10.1126/science.1124514
DO - 10.1126/science.1124514
M3 - Article
C2 - 16469881
AN - SCOPUS:33644850056
SN - 0036-8075
VL - 311
SP - 1471
EP - 1474
JO - Science
JF - Science
IS - 5766
ER -