Research Perspective Volume 10, Issue 12 pp 3657—3661
Autophagy delays progression of the two most frequent human monogenetic lethal diseases: cystic fibrosis and Wilson disease
- 1 Department of Health Sciences, University of Eastern Piedmont, Novara, Italy
- 2 European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan, Italy
- 3 Equipe11 Labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- 4 INSERM U1138, Centre de Recherche des Cordeliers, Paris, France
- 5 Université Paris Descartes, Paris, France
- 6 Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France
- 7 Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
- 8 Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden
received: December 10, 2018 ; accepted: December 15, 2018 ; published: December 19, 2018 ;https://doi.org/10.18632/aging.101736
How to Cite
Copyright: Maiuri and Kroemer. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.