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Control of autophagy as a therapy for neurodegenerative disease

Abstract

Autophagy is an intracellular degradation process that clears long-lived proteins and organelles from the cytoplasm. It involves the formation of double-membraned structures called autophagosomes that can engulf portions of cytoplasm containing oligomeric protein complexes and organelles, such as mitochondria. Autophagosomes fuse with lysosomes and their contents then are degraded. Failure of autophagy in neurons can result in the accumulation of aggregate-prone proteins and neurodegeneration. Pharmacological induction of autophagy can enhance the clearance of intracytoplasmic aggregate-prone proteins, such as mutant forms of huntingtin, and ameliorate pathology in cell and animal models of neurodegenerative diseases. In this Review, the autophagic machinery and the signaling pathways that regulate the induction of autophagy are described. The ways in which dysfunctions at multiple stages in the autophagic pathways contribute to numerous neurological disorders are highlighted through the use of examples of Mendelian and complex conditions, including Alzheimer disease, Parkinson disease and forms of motor neuron disease. The different ways in which autophagic pathways might be manipulated for the therapeutic benefit of patients with neurodegenerative disorders are also considered.

Key Points

  • Macroautophagy (also known as autophagy) is a process by which cytoplasmic substrates are sequestered within double-membraned vesicles called autophagosomes, which are then delivered to the lysosome for degradation

  • Autophagic dysfunction might contribute to the pathogenesis of numerous neurodegenerative diseases, including forms of Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease and Lafora disease

  • Autophagy is regulated by both mTOR-dependent and mTOR-independent pathways, which have multiple components that could be targeted for therapeutic manipulation of this degradative process

  • Patients with conditions that are associated with the accumulation of intracytoplasmic aggregate-prone proteins may benefit from pharmacological upregulation of autophagy

  • An advanced understanding of the pathways that regulate autophagy is required to maximize the potential of targeting autophagy for therapeutic purposes

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Figure 1: Stages of macroautophagy.
Figure 2: Signaling pathways involved in the regulation of autophagy.

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Acknowledgements

The authors are grateful to the Wellcome Trust for providing funding for the studentship of H. Harris and a Senior Fellowship for D. C. Rubinsztein, to the Medical Research Council for providing a program grant and a Medical Research Council/Wellcome Trust Strategic Award to D. C. Rubinsztein, and to the National Institute for Health Research Biomedical Research Center at Addenbrooke's Hospital. We also thank M. Renna for helpful comments on the manuscript.

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Correspondence to David C. Rubinsztein.

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D. C. Rubinsztein has received grant support from Lilly and Wyeth. H. Harris declares no competing interests.

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Harris, H., Rubinsztein, D. Control of autophagy as a therapy for neurodegenerative disease. Nat Rev Neurol 8, 108–117 (2012). https://doi.org/10.1038/nrneurol.2011.200

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