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Cited by 364Amyotrophic Lateral Sclerosis ResearchAutophagy in Disease and TherapyHereditary Neurological Disorders

Rapamycin treatment augments motor neuron degeneration in SOD1G93Amouse model of amyotrophic lateral sclerosis

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Zhang, Xiaojie, Li, Liang, Chen, Sheng, Yang, Dehua, Wang, Yi, Zhang, Xin, Wang, Zheng, Le, Weidong·2011·Autophagy
DOI 10.4161/auto.7.4.14541
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Abstract

Aberrant protein misfolding may contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS) but the detailed mechanisms are largely unknown. Our previous study has shown that autophagy is altered in the mouse model of ALS. In the present study, we systematically investigated the correlation of the autophagic alteration with the motor neurons (MNs) degeneration in the ALS mice. We have demonstrated that the autophagic protein marker LC3-II is markedly and specifically increased in the spinal cord MNs of the ALS mice. Electron microscopy and immunochemistry studies have shown that autophagic vacuoles are significantly accumulated in the dystrophic axons of spinal cord MNs of the ALS mice. All these changes in the ALS mice appear at the age of 90 d when the ALS mice display modest clinical symptoms; and they become prominent at the age of 120 d. The clinical symptoms are correlated with the progression of MNs degeneration. Moreover, we have found that p62/SQSTM1 is accumulated progressively in the spinal cord, indicating that the possibility of impaired autophagic flux in the SOD1(G93A) mice. Furthermore, to our surprise, we have found that treatment with autophagy enhancer rapamycin accelerates the MNs degeneration, shortens the life span of the ALS mice, and has no obvious effects on the accumulation of SOD1 aggregates. In addition, we have demonstrated that rapamycin treatment in the ALS mice causes more severe mitochondrial impairment, higher Bax levels and greater caspase-3 activation. These findings suggest that selective degeneration of MNs is associated with the impairment of the autophagy pathway and that rapamycin treatment may exacerbate the pathological processing through apoptosis and other mechanisms in the ALS mice.

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  • Rapamycin facilitates motor neuron degeneration and rapid disease progression in SOD1G93A ALS mice.

    “rapamycin facilitates motor neuron degeneration and rapid disease progression in SOD1G93A ALS mice [338]”

    From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [338]

  • Rapamycin and related MTOR inhibitors, as well as AKT inhibitors, are ineffective inducers of neuronal autophagy.

    “rapamycin and related MTOR inhibitors, as well as AKT inhibitors, are ineffective inducers of neuronal autophagy [338,384].”

    From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [338]

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Cited by 364

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Authors
Zhang, X., Li, L., Chen, S., Yang, D., Wang, Y., Zhang, X., Wang, Z., & Le, W.
Affiliations
  • Shanghai Jiao Tong University (CN)
  • Houston Methodist (US)
Corresponding author
Le, Weidong
ORCID
Venue
Autophagy
Publisher
Informa UK Limited
Published
2011-04
Volume
7
Issue
4
Pages
412-425
ISSN
  • 1554-8627 (ISSN-L)
  • 1554-8635
DOI
10.4161/auto.7.4.14541
OpenAlex
W1985403672
Cited by
364
References
0
Citations by year
2026: 4 · 2025: 16 · 2024: 10 · 2023: 19 · 2022: 17 · 2021: 22 · 2020: 30 · 2019: 26 · 2018: 32 · 2017: 27 · 2016: 30 · 2015: 36 · 2014: 34 · 2013: 33 · 2012: 17
FWCI
19.06
Type
journal article
Language
en
Open access
Locations
  • Autophagy (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Diana Helis Henry Medical Research Foundation
  • Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
  • Fudan University
  • National Key Research and Development Program of China (2010CB945200)
  • Shanghai Medical College, Fudan University
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
amyotrophic lateral sclerosis, SOD1 G93A mice, rapamycin, motor neuron degeneration, LC3-II, p62, autophagic flux, autophagosomes, mitochondrial dysfunction, apoptosis, Bax, caspase-3, protein misfolding, lifespan
MeSH terms
Sequestosome-1 Protein, Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Animals, Autophagy, Disease Models, Animal, Heat-Shock Proteins, Immunosuppressive Agents, Mitochondria, Motor Neurons, Poly(ADP-ribose) Polymerases, Spinal Cord, Superoxide Dismutase, Neurodegenerative Diseases, Sirolimus, Adaptor Proteins, Signal Transducing, bcl-2-Associated X Protein, Mice, Caspase 3, TOR Serine-Threonine Kinases

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