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Cited by 109Autophagy in Disease and TherapyHereditary Neurological DisordersAlzheimer's disease research and treatments

Atg9a deficiency causes axon-specific lesions including neuronal circuit dysgenesis

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Yamaguchi, Junji, Suzuki, Chigure, Nanao, Tomohisa, Kakuta, Soichirou, Ozawa, Kentarou, Tanida, Isei, Saitoh, Tatsuya, Sunabori, Takehiko +5 more·2018·Autophagy
DOI 10.1080/15548627.2017.1314897PMC PMC6070006
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Abstract

Conditional knockout mice for Atg9a, specifically in brain tissue, were generated to understand the roles of ATG9A in the neural tissue cells. The mice were born normally, but half of them died within one wk, and none lived beyond 4 wk of age. SQSTM1/p62 and NBR1, receptor proteins for selective autophagy, together with ubiquitin, accumulated in Atg9a-deficient neurosoma at postnatal d 15 (P15), indicating an inhibition of autophagy, whereas these proteins were significantly decreased at P28, as evidenced by immunohistochemistry, electron microscopy and western blot. Conversely, degenerative changes such as spongiosis of nerve fiber tracts proceeded in axons and their terminals that were occupied with aberrant membrane structures and amorphous materials at P28, although no clear-cut degenerative change was detected in neuronal cell bodies. Different from autophagy, diffusion tensor magnetic resonance imaging and histological observations revealed Atg9a-deficiency-induced dysgenesis of the corpus callosum and anterior commissure. As for the neurite extensions of primary cultured neurons, the neurite outgrowth after 3 d culturing was significantly impaired in primary neurons from atg9a-KO mouse brains, but not in those from atg7-KO and atg16l1-KO brains. Moreover, this tendency was also confirmed in Atg9a-knockdown neurons under an atg7-KO background, indicating the role of ATG9A in the regulation of neurite outgrowth that is independent of autophagy. These results suggest that Atg9a deficiency causes progressive degeneration in the axons and their terminals, but not in neuronal cell bodies, where the degradations of SQSTM1/p62 and NBR1 were insufficiently suppressed. Moreover, the deletion of Atg9a impaired nerve fiber tract formation.

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Crossref · 10.1080/15548627.2017.1314897

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  • Autophagy is inhibited in ATG9A KO animals, as suggested by accumulation of p62/SQSTM1, NBR1, and ubiquitin.

    “The observed accumulation of p62/SQSTM1, NBR1, and ubiquitin suggests that autophagy is inhibited in ATG9A KO animals [53, 54].”

    From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [53]

    The Results section (“Impairment of autophagy in neurons”; page not provided) reports accumulation of ubiquitin, SQSTM1 and NBR1 in neurons of CNS-specific atg9a-CKO mice at two weeks, supporting the inference of impaired autophagy. The claim omits that their accumulation decreased by four weeks; the paper says some autophagic degradation may occur after two weeks, so it does not support unqualified inhibition across the animals’ lifespan or tissues. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • ATG9A KO mice die at a very early developmental stage.

    “ATG9A KO mice die at a very early developmental stage [53, 54].”

    From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [53]

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Research works printed but not linked: 40

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Authors
Yamaguchi, J., Suzuki, C., Nanao, T., Kakuta, S., Ozawa, K., Tanida, I., Saitoh, T., Sunabori, T., Komatsu, M., Tanaka, K., Aoki, S., Sakimura, K., & Uchiyama, Y.
Affiliations
  • Juntendo University (JP)
  • Tokyo University of Science (JP)
  • Nara Medical University (JP)
  • Tokushima University (JP)
  • Niigata University (JP)
  • Tokyo Metropolitan Institute of Medical Science (JP)
  • Brain Research Institute, Niigata University (JP)
Corresponding author
Uchiyama, Yasuo
ORCID
Venue
Autophagy
Publisher
Informa UK Limited
Published
2018-03-06
Volume
14
Issue
5
Pages
764-777
ISSN
  • 1554-8627 (ISSN-L)
  • 1554-8635
DOI
10.1080/15548627.2017.1314897
PMC
PMC6070006
OpenAlex
W2615266298
Cited by
109
References
47
Citations by year
2026: 10 · 2025: 10 · 2024: 14 · 2023: 16 · 2022: 17 · 2021: 15 · 2020: 9 · 2019: 11 · 2018: 4 · 2017: 3
FWCI
5.78
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Autophagy (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
Ministry of Education, Culture, Sports, Science and Technology of Japan
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
ATG9A, selective autophagy, axonal degeneration, axon terminal degeneration, corpus callosum, anterior commissure, neurite outgrowth, p62, NBR1, autophagy inhibition, conditional knockout mice, ATG7, ATG16L1
MeSH terms
Autophagy-Related Proteins, Sequestosome-1 Protein, Animals, Axons, Cells, Cultured, Corpus Callosum, Membrane Proteins, Nerve Net, Phenotype, Proteins, Purkinje Cells, Neurites, Mice, Knockout, Integrases, Vesicular Transport Proteins, Intracellular Signaling Peptides and Proteins

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