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Macroautophagy in CNS health and disease

Abstract

Macroautophagy is an evolutionarily conserved process that delivers diverse cellular contents to lysosomes for degradation. As our understanding of this pathway grows, so does our appreciation for its importance in disorders of the CNS. Once implicated primarily in neurodegenerative events owing to acute injury and ageing, macroautophagy is now also linked to disorders of neurodevelopment, indicating that it is essential for both the formation and maintenance of a healthy CNS. In parallel to understanding the significance of macroautophagy across contexts, we have gained a greater mechanistic insight into its physiological regulation and the breadth of cargoes it can degrade. Macroautophagy is a broadly used homeostatic process, giving rise to questions surrounding how defects in this single pathway could cause diseases with distinct clinical and pathological signatures. To address this complexity, we herein review macroautophagy in the mammalian CNS by examining three key features of the process and its relationship to disease: how it functions at a basal level in the discrete cell types of the brain and spinal cord; which cargoes are being degraded in physiological and pathological settings; and how the different stages of the macroautophagy pathway intersect with diseases of neurodevelopment and adult-onset neurodegeneration.

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Fig. 1: Molecular overview of autophagy and related membrane trafficking events.
Fig. 2: Autophagy in cells of the CNS.
Fig. 3: Models of autophagy dysfunction in neurodegenerative diseases.

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Acknowledgements

The authors thank the members of the Yamamoto laboratory for helpful discussion. This work was supported by the NINDS F31 NS118897 (C.J.G.), NINDS RO1 NS063973 (A.Y.), NINDS RO1NS077111 (A.Y.), NINDS RO1 NS101663 (C.J.G. and A.Y.), NINDS R21 NS118891 (A.Y.), The Hereditary Disease Foundation with the Alexander Boyd and Jane Starke Boyd Charitable Foundation, Thompson Family Foundation, the Russell Berrie Foundation Initiative in the Neurobiology of Obesity at Columbia University and the MSTP Training grant 5T32GM007367 (C.J.G.).

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Correspondence to Ai Yamamoto.

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Nature Reviews Neuroscience thanks V. Nikoletopoulou, S. Soukup, who co-reviewed with S. Hernandez-Diaz, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Catabolism

The breakdown of complex molecules and structures into smaller units.

Endocytic

Pertaining to the internalization of substances into the cell. These membrane-bound structures include endosomes and multivesicular bodies.

SNARE protein

SNAP receptor, or SNARE, proteins form a large family of proteins that mediate vesicle fusion.

Activity dependent

Affected by synaptic transmission.

Ischaemia–reperfusion injury

Exacerbation of cellular dysfunction and death after the return of blood flow (reperfusion) to tissues that previously had an inadequate blood supply (ischaemia).

Upper and lower motor neurons

Upper motor neurons project from the motor cortex of the cerebrum and brainstem to form the corticospinal, corticobulbar and other tracts. Lower motor neurons project from the spinal cord to effector muscles to carry out a movement.

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Griffey, C.J., Yamamoto, A. Macroautophagy in CNS health and disease. Nat Rev Neurosci 23, 411–427 (2022). https://doi.org/10.1038/s41583-022-00588-3

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