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Cited by 614Autophagy in Disease and TherapyHereditary Neurological DisordersAlzheimer's disease research and treatments

Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration

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Komatsu, Masaaki, Wang, Qing Jun, Holstein, Gay R., Friedrich, Victor L., Iwata, Jun-ichi, Kominami, Eiki, Chait, Brian T., Tanaka, Keiji +1 more·2007·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0701311104PMC PMC1964831
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Abstract

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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  • Purkinje cells lacking the essential autophagy genes Atg5 or Atg7 die over time.

    “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]

    The paper states that Purkinje cell-specific deletion of Atg7 is followed by cell-autonomous Purkinje cell death (opening section; page unavailable). It does not establish the same outcome for Purkinje cells lacking Atg5, so the Atg5 part of the claim is unsupported by this source. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • Axons in the deep cerebellar nuclei of mice lacking Atg5 and Atg7 in Purkinje cells displayed increased membranous and vacuole-like structures.

    “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]

    The Results (Fig. 5) report increased aberrant membrane structures in Purkinje-cell axon terminals in the deep cerebellar nuclei after Atg7 deletion. But the Results (Fig. 6) say double-membrane vacuole-like structures were virtually absent in those mice, not increased. The cited study examines Purkinje-cell-specific Atg7 deletion, not Atg5 deletion. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Conditional deletion of the autophagy genes Atg5 or Atg7 in Purkinje cells leads to degeneration of these cells.

    “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]

    The Results report Purkinje cell-specific deletion of Atg7, and the paper states that the resulting axonal degeneration was followed by Purkinje cell death. The Discussion mentions Atg5 deletion in mutant mouse brains, but does not establish that Purkinje cell-specific Atg5 deletion caused degeneration of those cells. No page number is available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Mice with mutations in the autophagy genes Atg5, Atg7, FIP200 and Epg5 show the importance of autophagy in neurons and their stem cell precursors.

    “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]

  • In several in vivo models, neurons, particularly Purkinje cells, require functional autophagy to survive.

    “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]

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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)
ORCID
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
DOI
10.1073/pnas.0701311104
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
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
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
  • Health Sciences › Medicine › Physiology › 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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