Abstract
The proper folding of proteins to their functional forms is essential to cellular homeostasis. Perhaps not surprisingly, cells have evolved multiple pathways, some overlapping and others complementary, to resolve mis-folded proteins when they arise, ranging from refolding through the action of molecular chaperones to elimination through regulated proteolytic mechanisms. These protein quality control pathways are sufficient, under normal conditions, to maintain a functioning proteome, but in response to diverse environmental, genetic and/or stochastic events, protein mis-folding exceeds the corrective capacity of these pathways, leading to the accumulation of aggregates and ultimately toxicity. Particularly devastating examples of these effects include certain neurodegenerative diseases, such as Huntington's Disease, which are associated with the expansion of polyglutamine tracks in proteins. In these cases, protein mis-folding and aggregation are clear contributors to pathogenesis, but uncovering the precise mechanistic links between the two events remains an area of active research. Studies in the yeast Saccharomyces cerevisiae and other model systems have uncovered previously unanticipated complexity in aggregation pathways, the contributions of protein quality control processes to them and the cellular perturbations that result from them. Together these studies suggest that aggregate interactions and localization, rather than their size, are the crucial considerations in understanding the molecular basis of toxicity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 294-303 |
| Number of pages | 10 |
| Journal | Critical Reviews in Biochemistry and Molecular Biology |
| Volume | 49 |
| Issue number | 4 |
| DOIs | |
| State | Published - 2014 |
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Keywords
- Amyloid
- Chaperone
- Mis-folding
- PolyQ
- Prion
- Toxicity
ASJC Scopus subject areas
- Molecular Biology
- Biochemistry
- Medicine(all)
Cite this
Defining the limits : Protein aggregation and toxicity in vivo. / Holmes, William M.; Klaips, Courtney L.; Serio, Tricia R.
In: Critical Reviews in Biochemistry and Molecular Biology, Vol. 49, No. 4, 2014, p. 294-303.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Defining the limits
T2 - Protein aggregation and toxicity in vivo
AU - Holmes, William M.
AU - Klaips, Courtney L.
AU - Serio, Tricia R
PY - 2014
Y1 - 2014
N2 - The proper folding of proteins to their functional forms is essential to cellular homeostasis. Perhaps not surprisingly, cells have evolved multiple pathways, some overlapping and others complementary, to resolve mis-folded proteins when they arise, ranging from refolding through the action of molecular chaperones to elimination through regulated proteolytic mechanisms. These protein quality control pathways are sufficient, under normal conditions, to maintain a functioning proteome, but in response to diverse environmental, genetic and/or stochastic events, protein mis-folding exceeds the corrective capacity of these pathways, leading to the accumulation of aggregates and ultimately toxicity. Particularly devastating examples of these effects include certain neurodegenerative diseases, such as Huntington's Disease, which are associated with the expansion of polyglutamine tracks in proteins. In these cases, protein mis-folding and aggregation are clear contributors to pathogenesis, but uncovering the precise mechanistic links between the two events remains an area of active research. Studies in the yeast Saccharomyces cerevisiae and other model systems have uncovered previously unanticipated complexity in aggregation pathways, the contributions of protein quality control processes to them and the cellular perturbations that result from them. Together these studies suggest that aggregate interactions and localization, rather than their size, are the crucial considerations in understanding the molecular basis of toxicity.
AB - The proper folding of proteins to their functional forms is essential to cellular homeostasis. Perhaps not surprisingly, cells have evolved multiple pathways, some overlapping and others complementary, to resolve mis-folded proteins when they arise, ranging from refolding through the action of molecular chaperones to elimination through regulated proteolytic mechanisms. These protein quality control pathways are sufficient, under normal conditions, to maintain a functioning proteome, but in response to diverse environmental, genetic and/or stochastic events, protein mis-folding exceeds the corrective capacity of these pathways, leading to the accumulation of aggregates and ultimately toxicity. Particularly devastating examples of these effects include certain neurodegenerative diseases, such as Huntington's Disease, which are associated with the expansion of polyglutamine tracks in proteins. In these cases, protein mis-folding and aggregation are clear contributors to pathogenesis, but uncovering the precise mechanistic links between the two events remains an area of active research. Studies in the yeast Saccharomyces cerevisiae and other model systems have uncovered previously unanticipated complexity in aggregation pathways, the contributions of protein quality control processes to them and the cellular perturbations that result from them. Together these studies suggest that aggregate interactions and localization, rather than their size, are the crucial considerations in understanding the molecular basis of toxicity.
KW - Amyloid
KW - Chaperone
KW - Mis-folding
KW - PolyQ
KW - Prion
KW - Toxicity
UR - http://www.scopus.com/inward/record.url?scp=84904696676&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84904696676&partnerID=8YFLogxK
U2 - 10.3109/10409238.2014.914151
DO - 10.3109/10409238.2014.914151
M3 - Article
C2 - 24766537
AN - SCOPUS:84904696676
VL - 49
SP - 294
EP - 303
JO - Critical Reviews in Biochemistry and Molecular Biology
JF - Critical Reviews in Biochemistry and Molecular Biology
SN - 1040-9238
IS - 4
ER -