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Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration
Open accessAbstract
Autophagy is a regulated lysosomal degradation process that involves autophagosome formation and transport. Although recent evidence indicates that basal levels of autophagy protect against neurodegeneration, the exact mechanism whereby this occurs is not known. By using conditional knockout mutant mice, we report that neuronal autophagy is particularly important for the maintenance of local homeostasis of axon terminals and protection against axonal degeneration. We show that specific ablation of an essential autophagy gene, Atg7 , in Purkinje cells initially causes cell-autonomous, progressive dystrophy (manifested by axonal swellings) and degeneration of the axon terminals. Consistent with suppression of autophagy, no autophagosomes are observed in these dystrophic swellings, which is in contrast to accumulation of autophagosomes in the axonal dystrophic swellings under pathological conditions. Axonal dystrophy of mutant Purkinje cells proceeds with little sign of dendritic or spine atrophy, indicating that axon terminals are much more vulnerable to autophagy impairment than dendrites. This early pathological event in the axons is followed by cell-autonomous Purkinje cell death and mouse behavioral deficits. Furthermore, ultrastructural analyses of mutant Purkinje cells reveal an accumulation of aberrant membrane structures in the axonal dystrophic swellings. Finally, we observe double-membrane vacuole-like structures in wild-type Purkinje cell axons, whereas these structures are abolished in mutant Purkinje cell axons. Thus, we conclude that the autophagy protein Atg7 is required for membrane trafficking and turnover in the axons. Our study implicates impairment of axonal autophagy as a possible mechanism for axonopathy associated with neurodegeneration.
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“Interestingly, Purkinje cells lacking the essential autophagy genes Atg5 or Atg7 die over time2021.”
From Clec16a is Critical for Autolysosome Function and Purkinje Cell Survival (2016) · cites this paper as [20]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“axons in the deep cerebellar nuclei of mice lacking Atg5 and Atg7 in Purkinje cells displayed increased membranous and vacuole-like structures”
From Clec16a is Critical for Autolysosome Function and Purkinje Cell Survival (2016) · cites this paper as [20]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“For example, the conditional deletion of the autophagy genes Atg5 or Atg7 in Purkinje cells leads to degeneration of these cells2021.”
From Clec16a is Critical for Autolysosome Function and Purkinje Cell Survival (2016) · cites this paper as [20]
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“Mice with mutations in the autophagy genes Atg5, Atg7, FIP200 and Epg5 show the importance of autophagy in neurons and their stem cell precursors20212223.”
From Clec16a is Critical for Autolysosome Function and Purkinje Cell Survival (2016) · cites this paper as [20]
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“In several in vivo models, neurons, and in particular Purkinje cells, demonstrate a striking requirement for functional autophagy in order to survive.”
From Clec16a is Critical for Autolysosome Function and Purkinje Cell Survival (2016) · cites this paper as [20]
In the citing paper
“Purkinje-specific deletion of Atg7 (encoding an essential E1-like enzyme required for activating ATG12, ATG8, and LC3-I) results in Purkinje cell-autonomous axonal dystrophy and degeneration in mice [376].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [376]
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“These encompass Purkinje cells in the cerebellum (leading to progressive dystrophy) (Komatsu et al, 2007)”
From Autophagy in major human diseases (2021) · cites this paper as Komatsu et al, 2007
In the citing paper
“In fact, these autophagosome-like structures were previously reported in Atg7-deficient brains14.”
From Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice (2018) · cites this paper as [14]
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LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.
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Metadata
- Authors
- Komatsu, M., Wang, Q. J., Holstein, G. R., Friedrich, V. L., Iwata, J.-I., Kominami, E., Chait, B. T., Tanaka, K., & Yue, Z.
- Affiliations
- Juntendo University (JP)
- Rockefeller University (US)
- Icahn School of Medicine at Mount Sinai (US)
- *Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan;
- Tokyo Metropolitan Institute of Medical Science (JP)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-09-04
- Volume
- 104
- Issue
- 36
- Pages
- 14489-14494
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1964831
- OpenAlex
- W2120640283
- Cited by
- 614
- References
- 34
- Citations by year
- 2026: 12 · 2025: 24 · 2024: 25 · 2023: 24 · 2022: 25 · 2021: 42 · 2020: 40 · 2019: 49 · 2018: 39 · 2017: 44 · 2016: 39 · 2015: 32 · 2014: 39 · 2013: 32 · 2012: 43
- FWCI
- 16.81
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (RNS055683A)
- National Institute of Neurological Disorders and Stroke (R21NS055683)
- National Center for Research Resources (RR00862, P41RR000862, RR 022220, U54RR022220)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- autophagy, ATG7, axonal degeneration, Purkinje cells, axonal dystrophy, axonal swellings, autophagosomes, membrane trafficking, neurodegeneration, axonopathy, conditional knockout mice, Purkinje cell death
- MeSH terms
- Autophagy-Related Protein 7, Sequestosome-1 Protein, Animals, Autophagy, Axons, Cell Membrane, Heat-Shock Proteins, Homeostasis, Mice, Transgenic, Microtubule-Associated Proteins, Nerve Degeneration, Neuropeptides, Purkinje Cells, Spine, Genes, Reporter, Guanine Nucleotide Exchange Factors, Microscopy, Electron, Transmission, Cell Shape, Adaptor Proteins, Signal Transducing, Mice
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