Science Background

The folding of proteins into their correct three dimensional conformations is essential to normal cellular function and is determined by many factors including the primary amino acid sequence and the subcellular environment. Most proteins begin to fold as they are synthesized. Correct folding is required for catalytic activity, for incorporation into multisubunit complexes, and for translocation to the appropriate intracellular or extracellular compartment. The accuracy of protein folding is ensured and monitored by a dual quality control system. One component is an energy dependent chaperone system that prevents the aggregation of partially folded proteins and facilitates complete folding. The second is protein degradation (ubiquitin/proteosome) system that identifies and degrades improperly folded and damaged proteins.

Factors that tilt the balance between correctly folded proteins and misfolded proteins are common causes of disease. This balance can be perturbed by an age-related reduction in the efficiency of the quality control system and/or by the inheritance of mutations in the primary amino acid sequence of the protein. Both can lead to protein misfolding with subsequent deleterious effects including reduced catalytic activity, improper trafficking, and/or aggregation. Accumulation of misfolded proteins can overwhelm the quality control system leading to chronic induction of cellular stress responses or to formation of toxic aggregates that themselves lead to pathology.

The role of protein misfolding in the pathogenesis of human disease is an emerging and exciting field of research. Several previously unrelated diseases, such as prion diseases, diabetes, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and transthyretin amyloidosis share a common feature of aggregation and deposition of misfolded protein. Several inherited disorders, such as cystic fibrosis, lysosomal storage diseases, and type 2 diabetes, result from defective trafficking of a misfolded mutant protein.