Protein Misfolding and Disease
ERAD (endoplasmic reticulum associated degradation) is a cytoprotective pathway that surveys newly synthesized proteins in the endoplasmic reticulum (quality control) and selects terminally misfolded proteins for degradation by the proteasome. When the ERAD pathway is overwhelmed, misfolded protein accumulates leading to cell injury or death. Many diseases have been linked to genetic mutations that cause misfolding and accumulation of cytotoxic proteins within the cell.
Surfactant protein C (SP-C), a protein that is synthesized and secreted by alveolar epithelial cells, plays an important role in maintaining alveolar structure and the integrity of the air-blood barrier. Mutations in the gene encoding SP-C (SFTPC) were recently linked to the development of interstitial lung disease (ILD) in human patients.
The overall goal of research in the Weaver lab is to identify molecular pathways that link protein misfolding to ILD and to develop novel treatment strategies for this fatal disease.
Current projects are directed toward identification of:
- The "molecular machinery" that distinguishes between correctly and incorrectly folded SP-C in the ERAD pathway;
- The "molecular trigger" that leads to saturation of ERAD and accumulation of mutant SP-C in human patients with ILD;
- "Molecular chaperones" that specifically inhibit intracellular accumulation of mutant SP-C.
 Click to enlarge.
Mutations in the COOH-terminal domain of SP-C (blue) are associated with interstitial lung disease. |  Click to enlarge.
High expression of a transgene encoding mutant SP-C profoundly disrupts lung development in transgenic mice (top panels) compared to low expressing transgenic mice and wild type mice (bottom panels). |
Related Publications
Bridges JP, Xu Y, Na CL, Wong HR, and Weaver TE. Adaptation and increased susceptibility to infection associated with constitutive expression of misfolded SP-C. J Cell Biol 172: 395-407, 2006.
Bridges, JP, Wert, SE, Nogee, LM and Weaver, TE: Expression of a human surfactant protein C mutation associated with interstitial lung disease disrupts lung development in transgenic mice. Journal of Biological Chemistry 278:52739-52746, 2003.
Whitsett, JA and Weaver, TE: Hydrophobic surfactant proteins in lung function and disease. New England Journal of Medicine 347:2141-2148, 2002.
Conkright, JJ, Na, C-L and Weaver, TE: Overexpression of surfactant protein-C mature peptide causes neonatal lethality in transgenic mice. American Journal of Respiratory Cell and Molecular Biology 26:85-90, 2002.
