Protein folding problems and quality control systems are emphasized not only in exogenous protein expression but also in endogenous protein expression. In fact, many diseases are brought on as a result of abnormal protein folding and/or a strict cellular quality control system. These diseases are called “conformational diseases.” A large number of diseases are now recognized as conformational diseases, including cystic fibrosis, Alzheimer’s disease, Parkinson’s disease, and alpha-1 antitrypsin deficiency.
Potential Application of TapBoost for a Conformational Disease
TapBoost exploits the protein folding and cell quality control system. The unique molecular mechanism of TapBoost enables the potential treatment of a conformational disease.
Example – Alpha-1 antitrypsin deficiency
Alpha-1 antitrypsin (AAT; A1AT) deficiency is an autosomal genetic disorder that affects both genders. A single amino acid change (AAT-Z; Glu342Lys) accounts for over 90% of disease-causing alleles. AAT-Z results in a misfolded protease inhibitor that is not secreted normally, but instead accumulates in an intracellular polymerized form, which is toxic to hepatocytes. Low serum levels of AAT and the polymerization of AAT-Z predispose the lung and liver to pulmonary disease and liver cirrhosis, respectively. We expressed this mutant AAT (AAT-Z) in a mammalian cells and confirmed the poor secretion of AAT-Z compared to its wild type counterpart. Instead, AAT-Z was accumulated in a cell in accordance with many literatures. In order to seek the possibility of TapBoost technology for therapeutic application, AAT-Z and TapBoost protein were designed to force an association between AATZ and TapBoost protein. We found that AAT-Z was secreted poorly compared to normal (WT) AAT in the absence of TapBoost protein (lane 2 vs. lane 3), but it was secreted efficiently when co-expressed with TapBoost protein (lane 4). These results support our hypothesis that it may be possible to develop a disease-specific TapBoost application to rescue the disease phenotype.