Rapamycin treatment augments motor neuron degeneration in SOD1 G93A mouse model of amyotrophic lateral sclerosis

Xiaojie Zhang, Liang Li, Sheng Chen, Dehua Yang, Yi Wang, Xin Zhang, Zheng Wang, Weidong Le

Research output: Contribution to journalArticle

251 Scopus citations

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 SOD1G93A 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.

Original languageEnglish (US)
Pages (from-to)412-425
Number of pages14
JournalAutophagy
Volume7
Issue number4
DOIs
StatePublished - Apr 2011

Keywords

  • ALS
  • Apoptosis
  • Autophagy
  • Motor neuron degeneration
  • Protein aggregation

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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