Open AccessDOK 7 gene therapy enhances motor activity and life span in ALS model mice
Author(s) -
Miyoshi Sadanori,
Tezuka Tohru,
Arimura Sumimasa,
Tomono Taro,
Okada Takashi,
Yamanashi Yuji
Publication year - 2017
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201607298
Subject(s) - neuromuscular junction , amyotrophic lateral sclerosis , motor neuron , riluzole , neuroscience , synapse , biology , motor nerve , skeletal muscle , muscle atrophy , medicine , microbiology and biotechnology , endocrinology , disease , spinal cord
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 ( NMJ s), 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 Mu SK by the cytoplasmic protein Dok‐7 is essential for NMJ formation, and forced expression of Dok‐7 in muscle activates Mu SK and enlarges NMJ s. Here, we show that therapeutic administration of an adeno‐associated virus vector encoding the human DOK 7 gene suppressed motor nerve terminal degeneration at NMJ s together with muscle atrophy in the SOD 1‐G93A ALS mouse model. Ultimately, we show that DOK 7 gene therapy enhanced motor activity and life span in ALS model mice.