Autophagy delays progression of the two most frequent human monogenetic lethal diseases: cystic fibrosis and Wilson disease

Cystic fibrosis (CF) and Wilson disease (WD) are two monogenetic, recessively inherited lethal pathologies that are caused by ionic disequilibria. CF results from loss-of-function mutations in CF transmembrane conductance regulator (CFTR), a channel that conducts chloride across epithelial cell membranes, while WD is due to a deficiency of ATPase copper transporting beta (ATP7B), a plasma membrane protein that pumps out copper from cells. Recent evidence suggests that both diseases are linked to perturbations in autophagy. CFTR deficiency causes an inhibition of autophagic flux, thus locking respiratory epithelial cells in a pro-inflammatory state and subverting the bactericidal function of macrophages. WD is linked to an increase in autophagy, which, however, is insufficient to mitigate the cytotoxicity of copper. Pharmacological induction of autophagy may delay disease progression, as indicated by preclinical evidence (for CF and WD) and results from clinical trials, in particular in CF patients with the most frequent CTRT mutation (CFTRdel506). Thus, CF and WD exemplify pathologies in which insufficient autophagy plays a major role in determining the chronology of disease progression, much like the pace of ‘normal’ aging that is dictated by disabled autophagy as well.