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Potential therapeutic applications of autophagy

Nature Reviews Drug Discovery volume 6, pages 304–312 (2007)Cite this article

Key Points

  • Macroautophagy, which is generally referred to as autophagy, involves the largely non-specific autophagic sequestration of cytoplasm into a double- or multiple-membrane-delimited compartment, termed an autophagosome, which is of non-lysosomal or vacuolar origin.

  • Autophagy normally plays a role in development, innate immunity, tumour suppression and the elimination of microbial pathogens. Defects in autophagy can result in some types of cancer, neurodegneration and myopathies.

  • Autophagy has a cytoprotective role, but can also participate in type II programmed cell death. Too much autophagy can be just as deleterious as an insufficient level of autophagy. It is important to gain a full understanding of the regulatory pathways to maximize the possibility of modulating autophagy for therapeutic purposes.

  • Stimulation of autophagy, for example through the mammalian target of rapamycin (mTOR)-inhibitor rapamycin, is being explored for cancer treatment.

  • The autophagy-related (Atg) proteins that are the subcellular machinery for this process are conserved from yeast to human. There are currently no drugs that directly inhibit or activate the Atg proteins.

  • Conditions that are associated with the accumulation of misfolded or aberrant proteins, such as Huntington's disease, forms of dementia and subtypes of Parkinson's disease, might be particularly amenable to treatments that stimulate autophagy.

Abstract

Autophagy is a dynamic process of subcellular degradation, which has recently sparked great interest as it is now recognized to be involved in various developmental processes and various diseases including cancer and neurodegeneration. Autophagy can function as a cytoprotective mechanism; however, it also has the capacity to cause cell death. A better understanding of autophagy is needed to allow its manipulation for therapeutic purposes, and new insights into the molecular mechanisms of autophagy are now leading to the discovery of exciting new potential drug targets.

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Figure 1: Schematic overview of macroautophagy.
Figure 2: Considerations for pharmacological modulation of autophagy.
Figure 3: Small molecules that affect autophagy.

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Acknowledgements

D.C.R. is grateful for funding from the Medical Research Council (Programme Grant), Wellcome Trust (Senior Fellowship in Clinical Science, EU Framework VI (EUROSCA and Wyeth (who make rapamycins). D.J.K. is supported by a grant from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, CB2 2XY, UK

    David C. Rubinsztein

  2. Life Sciences Institute and Department of Pathology, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Jason E. Gestwicki

  3. Novartis Institutes for BioMedical Research, Cambridge, 02139, Massachusetts, USA

    Leon O. Murphy

  4. Life Sciences Institute and Departments of Molecular, Cellular and Developmental Biology and Biological Chemistry, University of Michigan, Ann Arbor

    Daniel J. Klionsky

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Competing interests

D.C.R. is an inventor on patents relating to the use of autophagy upregulation for treating neurodegenerative diseases. D.C.R. is grateful for funding from the Medical Research Council (Programme Grant), Wellcome Trust (Senior Fellowship in Clinical Science and EU Framework VI (EUROSCA) and Wyeth (who make rapamycins). None of these sponsors have reviewed this manuscript. D.J.K. is the Editor-in-Chief of the journal Autophagy and is supported by a Public Health Service Grant from the National Institutes of Health.

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Glossary

Phosphotidylinositol-3-kinases

Class I phosphotidylinositol (PtdIns)-3-kinases are composed of catalytic p110 subunits and p85 adaptors. The main product of the class I enzymes is PtdIns(3,4,5)P3. This PtdIns participates in inhibition of autophagy. The Class III PtdIns-3-kinase is Vps34, which is associated with a presumed regulatory protein kinase Vps15. The class III enzyme generates only PtdIns(3)-phosphate, which is stimulatory for autophagy.

Akt1

Akt1 (or protein kinase B) is a serine/threonine protein kinase that is activated by the phosphotidylinositol-3-kinase pathway that activates survival responses.

mTOR

(Mammalian target of rapamycin). A family of kinases that is conserved in all eukaryotes that are sensitive to rapamycin and function in nutrient-sensing signal transduction, regulate translation and promote cell-cycle progression.

Haploinsufficient

A gene that requires biallelic expression. Suppression of one allele would reduce the gene dosage below the critical level.

3-methyladenine

3-methyladenine is an inhibitor of class III phosphotidylinositol-3-kinases and blocks autophagy. This compound acts as a competitive inhibitor of ATP.

Bafilomycin A1

Bafilomycin A1 binds integral membrane subunits in the vacuolar-type ATPase located in the lysosome membrane. The resulting inhibition of proton translocation, elevates lysosomal pH and blocks autophagy.

Bcl-2

(B-cell CLL/lymphoma 2). The founding member of a family of apoptosis-regulating proteins. Many Bcl-2-family members regulate mitochondria-dependent steps in cell-death pathways, with some suppressing and others promoting the release of apoptogenic proteins from these organelles.

p53

A tumour-suppressor protein that is involved in the regulation of cell-cycle events, including apoptosis.

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Rubinsztein, D., Gestwicki, J., Murphy, L. et al. Potential therapeutic applications of autophagy. Nat Rev Drug Discov 6, 304–312 (2007). https://doi.org/10.1038/nrd2272

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