Abstract
The inherently error-prone nature of protein biosynthesis and turnover leads to a constant flux of destabilized proteins. Genetic mutations in conformational disease-associated proteins, as well as exposure to acute and chronic proteotoxic stresses, further increase the load of misfolded protein on the proteostasis network. During aging, this leads to enhanced instability of the proteome, failure to buffer destabilizing genetic mutations or polymorphisms, and cellular decline. The combination of cell-type-specific differences in the buffering capacity of the proteostasis network and destabilizing polymorphisms in the genetic background may account for some of the cell-type specificity observed in disease, even when the predominant disease-associated protein is widely expressed.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 23-32 |
| Number of pages | 10 |
| Journal | Current Opinion in Structural Biology |
| Volume | 20 |
| Issue number | 1 |
| DOIs | |
| State | Published - Feb 2010 |
Funding
E.A.K. was supported by an individual postdoctoral fellowship from the National Institutes of Health (NINDS); research in the laboratory of R.I.M. was supported by grants from the National Institutes of Health (NIGMS and NIA) , the HDSA Coalition for the Cure , and the ALS Association .
ASJC Scopus subject areas
- Molecular Biology
- Structural Biology