Autophagy and human disease: emerging themes

Abstract

Malfunction of autophagy, the process that mediates breakdown and recycling of intracellular components in lysosomes, has been linked to a variety of human diseases. As the number of pathologies associated with defective autophagy increases, emphasis has switched from the mere description of the status of autophagy in these conditions to a more mechanistic dissection of the autophagic changes. Understanding the reasons behind the autophagic defect, the immediate consequences of the autophagic compromise and how autophagy changes with the evolution of the disease has become a 'must,' especially now that manipulation of autophagy is being considered as a therapeutic strategy. Here, we comment on some of the common themes that have emerged from such detailed analyses of the interplay between autophagy and disease conditions.

Figure 1. Mammalian autophagic pathways

Scheme depicting the main autophagic pathways in mammals and the different steps of macroautophagy and chaperone-mediated autophagy (CMA), which constitute the main emphasis of this review. Hsc70: heat shock cognate protein of 70kDa; hsp90: heat shock protein of 90KDa; L2A: lysosome associated membrane protein type 2A; KFERQ motif: targeting motif; e-MI: endosomal microautophagy.

Figure 2. Autophagy-related human diseases

Scheme of organ-specific (left) and systemic (right) human diseases in which alterations in autophagy are discussed in this review. Red dot indicates primary autophagy defects and green dot autophagy changes secondary or reactive to disease. Mutations (m), polymorphisms (p) and haplo-insufficiencies (h) described in molecular components of the autophagic pathways in the respective diseases are indicated in blue.