MTOR-independent, autophagic enhancer trehalose prolongs motor neuron survival and ameliorates the autophagic flux defect in a mouse model of amyotrophic lateral sclerosis

Autophagy. 2014 Apr;10(4):588-602. doi: 10.4161/auto.27710. Epub 2014 Jan 15.


Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder caused by selective motor neuron degeneration. Abnormal protein aggregation and impaired protein degradation pathways may contribute to the disease pathogenesis. Although it has been reported that autophagy is altered in patients and animal model of ALS, little is known about the role of autophagy in motor neuron degeneration in this disease. Our previous study shows that rapamycin, an MTOR-dependent autophagic activator, accelerates disease progression in the SOD1(G93A) mouse model of ALS. In the present report, we have assessed the role of the MTOR-independent autophagic pathway in ALS by determining the effect of the MTOR-independent autophagic inducer trehalose on disease onset and progression, and on motor neuron degeneration in SOD1(G93A) mice. We have found that trehalose significantly delays disease onset prolongs life span, and reduces motor neuron loss in the spinal cord of SOD1(G93A) mice. Most importantly, we have documented that trehalose decreases SOD1 and SQSTM1/p62 aggregation, reduces ubiquitinated protein accumulation, and improves autophagic flux in the motor neurons of SOD1(G93A) mice. Moreover, we have demonstrated that trehalose can reduce skeletal muscle denervation, protect mitochondria, and inhibit the proapoptotic pathway in SOD1(G93A) mice. Collectively, our study indicated that the MTOR-independent autophagic inducer trehalose is neuroprotective in the ALS model and autophagosome-lysosome fusion is a possible therapeutic target for the treatment of ALS.

Keywords: Cu/Zn superoxide dismutase 1; amyotrophic lateral sclerosis; autophagosome-lysosome fusion; autophagy; trehalose.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism*
  • Animals
  • Autophagy / drug effects*
  • Cell Survival
  • Disease Models, Animal
  • Male
  • Mice
  • Mice, Transgenic
  • Motor Neurons / drug effects*
  • Motor Neurons / pathology
  • Spinal Cord / metabolism*
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • Trehalose / pharmacology*


  • Trehalose
  • Superoxide Dismutase
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse