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Cited by 85Autophagy in Disease and TherapyCervical and Thoracic MyelopathyAmyotrophic Lateral Sclerosis Research

Accumulation of p62 in degenerated spinal cord under chronic mechanical compression: Functional analysis of p62 and autophagy in hypoxic neuronal cells

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Tanabe, Fumito, Yone, Kazunori, Kawabata, Naoya, Sakakima, Harutoshi, Matsuda, Fumiyo, Ishidou, Yasuhiro, Maeda, Shingo, Abematsu, Masahiko +2 more·2011·Autophagy
DOI 10.4161/auto.7.12.17892PMC PMC3288020
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Abstract

Intracellular accumulation of altered proteins, including p62 and ubiquitinated proteins, is the basis of most neurodegenerative disorders. The relationship among the accumulation of altered proteins, autophagy, and spinal cord dysfunction by cervical spondylotic myelopathy has not been clarified. We examined the expression of p62 and autophagy markers in the chronically compressed spinal cord of tiptoe-walking Yoshimura mice. In addition, we examined the expression and roles of p62 and autophagy in hypoxic neuronal cells. Western blot analysis showed the accumulation of p62, ubiquitinated proteins, and microtubule-associated protein 1 light chain 3 (LC3), an autophagic marker, in the compressed spinal cord. Immunohistochemical examinations showed that p62 accumulated in neurons, axons, astrocytes, and oligodendrocytes. Electron microscopy showed the expression of autophagy markers, including autolysosomes and autophagic vesicles, in the compressed spinal cord. These findings suggest the presence of p62 and autophagy in the degenerated compressed spinal cord. Hypoxic stress increased the expression of p62, ubiquitinated proteins, and LC3-II in neuronal cells. In addition, LC3 turnover assay and GFP-LC3 cleavage assay showed that hypoxic stress increased autophagy flux in neuronal cells. These findings suggest that hypoxic stress induces accumulation of p62 and autophagy in neuronal cells. The forced expression of p62 decreased the number of neuronal cells under hypoxic stress. These findings suggest that p62 accumulation under hypoxic stress promotes neuronal cell death. Treatment with 3-methyladenine, an autophagy inhibitor decreased the number of neuronal cells, whereas lithium chloride, an autophagy inducer increased the number of cells under hypoxic stress. These findings suggest that autophagy promotes neuronal cell survival under hypoxic stress. Our findings suggest that pharmacological inducers of autophagy may be useful for treating cervical spondylotic myelopathy patients.

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  • In the spinal cord injury model, single cells show a dramatic increase in LC3-positive autophagosomes and autophagolysosomes.

    “Analysis of single cells indicated a dramatic increase in the amount of LC3-positive autophagosomes and autophagolysosomes in this disease model (Figure 5b, right panels), confirming previous observations (examples in Sekiguchi et al.,33 Tanabe et al.37).”

    From Measurement of autophagy flux in the nervous system in vivo (2013) · cites this paper as Tanabe et al.37

    The Results report increased LC3 expression and the presence of autophagosomes and autolysosomes in chronically compressed mouse spinal cord, supporting the citation as an example of previous observations. They do not report a dramatic increase in LC3-positive autophagosomes and autolysosomes measured in single spinal-cord cells; the single-cell GFP-LC3 puncta measurements were made in cells subjected to hypoxia. (LLM, conf=0.85)

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Cited by

Sorted by citations

Authors
Tanabe, F., Yone, K., Kawabata, N., Sakakima, H., Matsuda, F., Ishidou, Y., Maeda, S., Abematsu, M., Komiya, S., & Setoguchi, T.
Affiliations
Kagoshima University (JP)
Corresponding author
Setoguchi, Takao
ORCID
Venue
Autophagy
Publisher
Informa UK Limited
Published
2011-12
Volume
7
Issue
12
Pages
1462-1471
ISSN
  • 1554-8627 (ISSN-L)
  • 1554-8635
DOI
10.4161/auto.7.12.17892
PMC
PMC3288020
OpenAlex
W1981591235
Cited by
85
References
4
Citations by year
2025: 8 · 2024: 3 · 2023: 10 · 2022: 5 · 2021: 10 · 2020: 6 · 2019: 3 · 2018: 7 · 2017: 5 · 2016: 6 · 2015: 9 · 2014: 6 · 2013: 3 · 2012: 4
FWCI
3.13
Type
journal article
Language
en
Open access
Locations
  • Autophagy (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Kagoshima University
  • Japan Society for the Promotion of Science (20591786, 22591663, 19591725, 21591919, 21591920)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Surgery › Cervical and Thoracic Myelopathy
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
p62, spinal cord degeneration, cervical spondylotic myelopathy, hypoxic stress, neuronal cell death, ubiquitinated proteins, LC3, autophagic flux, 3-methyladenine, lithium chloride, neurodegeneration
MeSH terms
Sequestosome-1 Protein, Animals, Astrocytes, Autophagy, Axons, Cell Count, Cervical Vertebrae, Heat-Shock Proteins, Lysosomes, Microtubule-Associated Proteins, Nerve Degeneration, Neurons, Oligodendroglia, Phagosomes, Spinal Cord, Spinal Cord Compression, Stress, Physiological, Stress, Mechanical, Cell Hypoxia, Up-Regulation, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Ubiquitinated Proteins

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