MTOR-independent, autophagic enhancer trehalose prolongs motor neuron survival and ameliorates the autophagic flux defect in a mouse model of amyotrophic lateral sclerosis.
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.
Institute of Neurology; Ruijin Hospital; Jiao Tong University School of Medicine; Shanghai, China; The Key Laboratory of Stem Cell Biology; Institute of Health Sciences; Shanghai Institutes for Biological Sciences; Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine; Shanghai, China.
Xiaojie
X
Zhang
Institute of Neurology; Ruijin Hospital; Jiao Tong University School of Medicine; Shanghai, China; Department of Neurology; Baylor College of Medicine; Houston, TX USA.
Sheng
S
Chen
Institute of Neurology; Ruijin Hospital; Jiao Tong University School of Medicine; Shanghai, China.
Lin
L
Song
The Key Laboratory of Stem Cell Biology; Institute of Health Sciences; Shanghai Institutes for Biological Sciences; Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine; Shanghai, China.
Yu
Y
Tang
Institute of Neurology; Ruijin Hospital; Jiao Tong University School of Medicine; Shanghai, China.
Yufei
Y
Shen
The Key Laboratory of Stem Cell Biology; Institute of Health Sciences; Shanghai Institutes for Biological Sciences; Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine; Shanghai, China.
Li
L
Jia
Institute of Neurology; Ruijin Hospital; Jiao Tong University School of Medicine; Shanghai, China; The Key Laboratory of Stem Cell Biology; Institute of Health Sciences; Shanghai Institutes for Biological Sciences; Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine; Shanghai, China; The First Affiliated Hospital; Dalian Medical University; Dalian, China.
Weidong
W
Le
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002470:Cell Survival; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects* / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014199:Trehalose / Q000494:pharmacology*
D014199:Trehalose; D013482:Superoxide Dismutase; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
Cu/Zn superoxide dismutase 1; amyotrophic lateral sclerosis; autophagosome-lysosome fusion; autophagy; trehalose