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  • Review Article
  • Published:

Compromised autophagy and neurodegenerative diseases

Key Points

  • Autophagy is an intracellular protein degradation pathway in which substrates to be degraded are surrounded by a double membrane and trafficked to lysosomes. Aggregate-prone proteins involved in neurodegenerative diseases are substrates for degradation by this pathway.

  • Autophagic dysfunction is increasingly being associated with the pathogenesis of neurodegenerative diseases. A recent and direct example is that mutations in the autophagy gene encoding WIPI4 (WDR45) cause the disease β-propeller protein-associated neurodegeneration (BPAN).

  • Genetic variants associated with neurodegenerative diseases have been identified that affect many aspects of the autophagic pathway, including control of initiation (via Beclin 1 interactions), sequestration of substrates into autophagosomes, trafficking of autophagosomes to lysosomes and the degradative capacity of lysosomes.

  • Although many perturbations in autophagy have been identified, it remains largely unclear how this contributes to disease pathogenesis and progression.

  • Induction of autophagy can be protective in models of neurodegenerative diseases. Thus, understanding how autophagy is affected in these diseases is vital to facilitate the successful development of novel therapeutics that target the autophagy pathway.

Abstract

Most neurodegenerative diseases that afflict humans are associated with the intracytoplasmic deposition of aggregate-prone proteins in neurons and with mitochondrial dysfunction. Autophagy is a powerful process for removing such proteins and for maintaining mitochondrial homeostasis. Over recent years, evidence has accumulated to demonstrate that upregulation of autophagy may protect against neurodegeneration. However, autophagy dysfunction has also been implicated in the pathogenesis of various diseases. This Review summarizes the progress that has been made in our understanding of how perturbations in autophagy are linked with neurodegenerative diseases and the potential therapeutic strategies resulting from the modulation of this process.

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Figure 1: Overview of the autophagy pathway and the sites of action of disease-associated proteins.
Figure 2: Initiation signals for mitophagy.

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Acknowledgements

The authors are grateful for funding from a Wellcome Trust Principal Research Fellowship (D.C.R.), a Wellcome Trust and Medical Research Council (MRC) Strategic Grant on neurodegeneration, a Wellcome Trust Strategic Award to the Cambridge Institute for Medical Research, the Alzheimer's disease National Institute for Health Research (NIHR) Biomedical Research Unit at Addenbrooke's Hospital, the Tau Consortium and Alzheimer's Research UK.

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Correspondence to David C. Rubinsztein.

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D.C.R. has received consultancy fees from GlaxoSmithKline, E3Bio and Bioblast and funding for research from MedImmune.

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Glossary

Tauopathies

A group of neurodegenerative diseases that are characterized by the prominent accumulation of tau protein in the CNS.

Ubiquitin–proteasome system

A cellular protein degradation system in which proteins tagged with ubiquitin, a small regulatory protein that is covalently attached to a target protein, are broken down by an enzyme complex called the proteasome.

Risk factors

Factors (in this article, alterations in DNA sequences) that may increase the chance of developing a disease.

Lysosome

An intracellular membrane-bound organelle containing hydrolytic enzymes that are capable of breaking down proteins and other cellular components.

Endocytic pathway

A general term to describe the vesicle trafficking routes by which cells internalize molecules from the plasma membrane.

Polymorphisms

The existence of multiple variants of a DNA sequence that occur within different individuals in the population, with no sequence being regarded as the standard sequence.

Multivesicular bodies

A type of late endosome containing internal vesicles.

Lewy bodies

Protein aggregates found within neurons in patients with certain neurodegenerative diseases, including Parkinson disease and Lewy body dementia.

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Menzies, F., Fleming, A. & Rubinsztein, D. Compromised autophagy and neurodegenerative diseases. Nat Rev Neurosci 16, 345–357 (2015). https://doi.org/10.1038/nrn3961

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