期刊
AUTOPHAGY
卷 10, 期 4, 页码 588-602出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/auto.27710
关键词
amyotrophic lateral sclerosis; Cu; Zn superoxide dismutase 1; autophagy; trehalose; autophagosome-lysosome fusion
类别
资金
- National Nature Science Foundation [81000541, 81200977]
- National Basic Research Program [2011CB510003]
- PhD Innovation Fund of Shanghai Jiaotong University school of Medicine [BXJ201218]
- Specialized Research Fund for the Doctoral Program of Higher Education of China [20120073110077]
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.
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