Cited by 209Autophagy in Disease and TherapySpinal Cord Injury ResearchEndoplasmic Reticulum Stress and Disease

Disrupted autophagy after spinal cord injury is associated with ER stress and neuronal cell death

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Liu, S, Sarkar, C, Dinizo, M, Faden, A I, Koh, E Y, Lipinski, M M, Wu, J·2015·Cell Death & Disease

Abstract

Autophagy is a catabolic mechanism facilitating degradation of cytoplasmic proteins and organelles in a lysosome-dependent manner. Autophagy flux is necessary for normal neuronal homeostasis and its dysfunction contributes to neuronal cell death in several neurodegenerative diseases. Elevated autophagy has been reported after spinal cord injury (SCI); however, its mechanism, cell type specificity and relationship to cell death are unknown. Using a rat model of contusive SCI, we observed accumulation of LC3-II-positive autophagosomes starting at posttrauma day 1. This was accompanied by a pronounced accumulation of autophagy substrate protein p62, indicating that early elevation of autophagy markers reflected disrupted autophagosome degradation. Levels of lysosomal protease cathepsin D and numbers of cathepsin-D-positive lysosomes were also decreased at this time, suggesting that lysosomal damage may contribute to the observed defect in autophagy flux. Normalization of p62 levels started by day 7 after SCI, and was associated with increased cathepsin D levels. At day 1 after SCI, accumulation of autophagosomes was pronounced in ventral horn motor neurons and dorsal column oligodendrocytes and microglia. In motor neurons, disruption of autophagy strongly correlated with evidence of endoplasmic reticulum (ER) stress. As autophagy is thought to protect against ER stress, its disruption after SCI could contribute to ER-stress-induced neuronal apoptosis. Consistently, motor neurons showing disrupted autophagy co-expressed ER-stress-associated initiator caspase 12 and cleaved executioner caspase 3. Together, these findings indicate that SCI causes lysosomal dysfunction that contributes to autophagy disruption and associated ER-stress-induced neuronal apoptosis.

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  • Oligodendrocyte autophagy may play a necessary but insufficient role in post-injury repair of the spinal cord.

    “These observations suggest that oligodendrocyte autophagy may play a necessary but insufficient role in post-injury repair of the spinal cord [453],”
  • Excessive autophagy in oligodendrocytes may lead to neuronal toxicity in a non-cell autonomous manner.

    “but excessive autophagy in oligodendrocytes may lead to neuronal toxicity in a non-cell autonomous manner.”

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Authors
Liu, S., Sarkar, C., Dinizo, M., Faden, A. I., Koh, E. Y., Lipinski, M. M., & Wu, J.
Affiliations
University of Maryland, Baltimore (US)
Corresponding author
Lipinski, M M
Venue
Cell Death & Disease
Published
2015-01-08
Volume
6
Issue
1
Pages
e1582-e1582
ISSN
2041-4889 (ISSN-L)
OpenAlex
W2095421072
Cited by
209
References
48
Citations by year
2026: 9 · 2025: 14 · 2024: 15 · 2023: 18 · 2022: 23 · 2021: 22 · 2020: 21 · 2019: 22 · 2018: 17 · 2017: 18 · 2016: 22 · 2015: 8
FWCI
16.92
Type
journal article
Language
en
Open access
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Nursing Research (R01NR013601)
  • National Institute of Neurological Disorders and Stroke (R01NS091218, R01NS054221)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords
spinal cord injury, autophagy, endoplasmic reticulum stress, neuronal apoptosis, lysosomal dysfunction, cathepsin D, p62, autophagosomes, motor neurons, oligodendrocytes, microglia, caspase-12, caspase-3, contusive injury
MeSH terms
Animals, Autophagy, Lysosomes, Male, Neurons, Oligodendroglia, Phagosomes, Spinal Cord Injuries, Rats, Sprague-Dawley, Apoptosis, Microglia, Endoplasmic Reticulum Stress, White Matter, Gray Matter

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