期刊
EMBO MOLECULAR MEDICINE
卷 9, 期 7, 页码 880-889出版社
WILEY
DOI: 10.15252/emmm.201607298
关键词
amyotrophic lateral sclerosis; DOK7; gene therapy; neuromuscular junction
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan [B-15]
- Japan Agency for Medical Research and Development [16ek0109003h0103, 16ek0109003h0003]
- [JP268885]
- [JP25110711]
- Grants-in-Aid for Scientific Research [26293328, 16K14575] Funding Source: KAKEN
Amyotrophic lateral sclerosis (ALS) is a progressive, multifactorial motor neurodegenerative disease with severe muscle atrophy. The glutamate release inhibitor riluzole is the only medication approved by the FDA, and prolongs patient life span by a few months, testifying to a strong need for new treatment strategies. In ALS, motor neuron degeneration first becomes evident at the motor nerve terminals in neuromuscular junctions (NMJs), the cholinergic synapse between motor neuron and skeletal muscle; degeneration then progresses proximally, implicating the NMJ as a therapeutic target. We previously demonstrated that activation of muscle-specific kinase MuSK by the cytoplasmic protein Dok-7 is essential for NMJ formation, and forced expression of Dok-7 in muscle activates MuSK and enlarges NMJs. Here, we show that therapeutic administration of an adeno-associated virus vector encoding the human DOK7 gene suppressed motor nerve terminal degeneration at NMJs together with muscle atrophy in the SOD1G93A ALS mouse model. Ultimately, we show that DOK7 gene therapy enhanced motor activity and life span in ALS model mice.
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