ABSTRACT
Chronic obstructive pulmonary disease (COPD) is currently the ninth leading cause of death in France and is predicted to become the third leading cause of worldwide morbidity and mortality by 2020. Risk factors for COPD include exposure to tobacco, dusts and chemicals, asthma and alpha-1 antitrypsin deficiency. This genetic disease, significantly under-diagnosed and under-recognized, affects 1 in 2500 live births and is an important cause of lung and, occasionally, liver disease. Alpha-1 antitrypsin deficiency is a pathology of proteostasis-mediated protein folding and trafficking pathways. To date, there are only palliative therapeutic approaches for the symptoms associated with this hereditary disorder. Therefore, a more detailed understanding is required of the folding and trafficking biology governing alpha-1 antitrypsin biogenesis and its response to drugs. Here, we review the cell biological, biochemical and biophysical properties of alpha-1 antitrypsin and its variants, and we suggest that alpha-1 antitrypsin deficiency is an example of cell autonomous and non-autonomous challenges to proteostasis. Finally, we review emerging strategies that may be used to enhance the proteostasis system and protect the lung from alpha-1 antitrypsin deficiency.