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Neurobiol Dis. 2019 Apr;124:340-352. doi: 10.1016/j.nbd.2018.12.002. Epub 2018 Dec 4.

Muscle specific kinase (MuSK) activation preserves neuromuscular junctions in the diaphragm but is not sufficient to provide a functional benefit in the SOD1G93A mouse model of ALS.

Author information

1
Departments of Neuroscience, Genentech, South San Francisco, CA, USA.
2
Departments of Biomedical Imaging, Genentech, South San Francisco, CA, USA.
3
Departments of Microchemistry, Proteomics, and Lipidomics, Genentech, South San Francisco, CA, USA.
4
Departments of Preclinical and Translational Pharmacokinetics, Genentech, South San Francisco, CA, USA.
5
Departments of Pathology, Genentech, South San Francisco, CA, USA.
6
Departments of Antibody Discovery, Genentech, South San Francisco, CA, USA.
7
Departments of Neuroscience, Genentech, South San Francisco, CA, USA. Electronic address: easton.amy@gene.com.

Abstract

Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons, is characterized by rapid decline of motor function and ultimately respiratory failure. As motor neuron death occurs late in the disease, therapeutics that prevent the initial disassembly of the neuromuscular junction may offer optimal functional benefit and delay disease progression. To test this hypothesis, we treated the SOD1G93A mouse model of ALS with an agonist antibody to muscle specific kinase (MuSK), a receptor tyrosine kinase required for the formation and maintenance of the neuromuscular junction. Chronic MuSK antibody treatment fully preserved innervation of the neuromuscular junction when compared with control-treated mice; however, no preservation of diaphragm function, motor neurons, or survival benefit was detected. These data show that anatomical preservation of neuromuscular junctions in the diaphragm via MuSK activation does not correlate with functional benefit in SOD1G93A mice, suggesting caution in employing MuSK activation as a therapeutic strategy for ALS patients.

KEYWORDS:

Amyotrophic lateral sclerosis; Diaphragm; Motor Neuron; Muscle specific kinase (MuSK); Neuromuscular junction; Respiration; SOD1

PMID:
30528255
DOI:
10.1016/j.nbd.2018.12.002

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