Targeting autophagy in disease: established and new strategies

Abstract

Macroautophagy/autophagy is an evolutionarily conserved pathway responsible for clearing cytosolic aggregated proteins, damaged organelles or invading microorganisms. Dysfunctional autophagy leads to pathological accumulation of the cargo, which has been linked to a range of human diseases, including neurodegenerative diseases, infectious and autoimmune diseases and various forms of cancer. Cumulative work in animal models, application of genetic tools and pharmacologically active compounds, has suggested the potential therapeutic value of autophagy modulation in disease, as diverse as Huntington, Salmonella infection, or pancreatic cancer. Autophagy activation versus inhibition strategies are being explored, while the role of autophagy in pathophysiology is being studied in parallel. However, the progress of preclinical and clinical development of autophagy modulators has been greatly hampered by the paucity of selective pharmacological agents and biomarkers to dissect their precise impact on various forms of autophagy and cellular responses. Here, we summarize established and new strategies in autophagy-related drug discovery and indicate a path toward establishing a more efficient discovery of autophagy-selective pharmacological agents. With this knowledge at hand, modern concepts for therapeutic exploitation of autophagy might become more plausible.

The mTOR–lysosome axis at the centre of ageing

“…Much has been learned about the basic mechanisms that drive autophagy, its effects on the hallmarks of ageing, and how it can be targeted using both pharmacological and dietary interventions. Even though the lysosome–autophagy pathway is now at a place where it is attracting attention from many research laboratories and even the private sector [ 185 , 186 ], translation of this knowledge to promote healthy ageing has not yet been realized.…”

EF24 exerts cytotoxicity against NSCLC via inducing ROS accumulation

“…This type of mitochondrial damage could initiate autophagy to removal dysfunctional mitochondria. SQSTM1 is a selective autophagic adaptor that can be incorporated with LC3B (an important marker of autophagy) and then be degraded by lysosomal hydrolyses [ 24 ]. As shown in Fig.…”

Therapeutic Targeting of Immune Cell Autophagy in Multiple Sclerosis: Russian Roulette or Silver Bullet?

“…The studies reviewed here identify autophagy as a promising therapeutic target in MS and other autoimmune diseases. Although pharmacological autophagy modulators offer feasible solutions, the available drugs are often not specific to autophagy (76). It is also worth noting that systemic autophagy inhibition may cause the aggregation of misfolded proteins in neurons, leading to neurodegenerative diseases (77).…”