Therapeutic targeting of autophagy in neurodegenerative and infectious diseases

Abstract

Autophagy is a conserved process that uses double-membrane vesicles to deliver cytoplasmic contents to lysosomes for degradation. Although autophagy may impact many facets of human biology and disease, in this review we focus on the ability of autophagy to protect against certain neurodegenerative and infectious diseases. Autophagy enhances the clearance of toxic, cytoplasmic, aggregate-prone proteins and infectious agents. The beneficial roles of autophagy can now be extended to supporting cell survival and regulating inflammation. Autophagic control of inflammation is one area where autophagy may have similar benefits for both infectious and neurodegenerative diseases beyond direct removal of the pathogenic agents. Preclinical data supporting the potential therapeutic utility of autophagy modulation in such conditions is accumulating.

Figure 1.

Schematic of autophagy. Activation of AMPK and/or inhibition of mTORC1 by various stress signals induces activation of the ATG1–ULK1 complex, which positively regulates the activity of the VPS34 complex via phosphorylation-dependent mechanisms. Class III PI3K VPS34 provides PI3P to the phagophore, which seems to define the LC3-lipidation sites by assisting in the recruitment of the ATG12–ATG5–ATG16L1 complex to the membrane (asterisks). After the binding of ATG12–ATG5–ATG16L1 complex to the phagophore and LC3 conjugation to PE (LC3-II), the membrane elongates and engulfs portions of the cytoplasm, ultimately leading to the formation of the complete autophagosome. Proteins such as p62, NDP52, and NBR1 confer substrate selectivity to the pathway by establishing a bridge between LC3-II and specific ubiquitinated cargo (e.g., aggregates, microbes, mitochondria, and peroxisomes), through their LIR and UBA domains, respectively. In the final step of the process, autophagosomes fuse with lysosomes, resulting in the degradation of the vesicle contents. AMPK, AMP-activated protein kinase; mTORC1, mechanistic target of rapamycin complex 1; ULK, Unc-51-like kinase; VPS34, phosphatidylinositol 3-kinase VPS34; PI3P, phosphatidylinositol 3-phosphate; PE, phosphatidylethanolamine; LIR, LC3-interacting region; UBA, ubiquitin associated domain.

Figure 2.

Protective roles of autophagy in neurodegenerative and infectious diseases. A major role for autophagy in neurodegenerative and infectious diseases involves the clearance of toxic aggregate-prone proteins and infectious agents, respectively. However, it also exerts ancillary beneficial roles by controlling cell death and exacerbated inflammatory responses associated with these pathologies.