Glycoprotein nonmetastatic melanoma protein B ameliorates skeletal muscle lesions in a SOD1G93A mouse model of amyotrophic lateral sclerosis.

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons and subsequent muscular atrophy. The quality of life of patients with ALS is significantly improved by ameliorating muscular symptoms. We previously reported that glycoprotein nonmetastatic melanoma protein B (GPNMB; osteoactivin) might serve as a target for ALS therapy. In the present study, superoxide dismutase 1/glycine residue 93 changed to alanine (SOD1(G93A) ) transgenic mice were used as a model of ALS. Expression of the C-terminal fragment of GPNMB was increased in the skeletal muscles of SOD1(G93A) mice and patients with sporadic ALS. SOD1(G93A) /GPNMB transgenic mice were generated to determine whether GPNMB expression ameliorates muscular symptoms. The weight and cross-sectional area of the gastrocnemius muscle, number and cross-sectional area of myofibers, and denervation of neuromuscular junctions were ameliorated in SOD1(G93A) /GPNMB vs. SOD1(G93A) mice. Furthermore, direct injection of a GPNMB expression plasmid into the gastrocnemius muscle of SOD1(G93A) mice increased the numbers of myofibers and prevented myofiber atrophy. These findings suggest that GPNMB directly affects skeletal muscle and prevents muscular pathology in SOD1(G93A) mice and may therefore serve as a target for therapy of ALS.

• Authors: Yuki Nagahara, Masamitsu Shimazawa, Hirotaka Tanaka, Yoko Ono, Yasuhiro Noda, Kazuki Ohuchi, Kazuhiro Tsuruma, Masahisa Katsuno, Gen Sobue, Hideaki Hara
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 93 Issue 10 Pg. 1552-66 (Oct 2015) ISSN: 1097-4547 [Electronic] United States
• PMID: 26140698 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 Wiley Periodicals, Inc.

Chemical References

• GPNMB protein, human
• Membrane Glycoproteins
• Synaptophysin
• SOD1 G93A protein
• Superoxide Dismutase

Topics

• Aged
• Amyotrophic Lateral Sclerosis (complications, genetics, pathology)
• Animals
• Disease Models, Animal
• Female
• Gene Expression Regulation (drug effects, genetics)
• Gene Transfer Techniques
• Humans
• Male
• Membrane Glycoproteins (genetics, metabolism, therapeutic use)
• Mice
• Mice, Transgenic
• Muscle, Skeletal (metabolism, pathology)
• Muscular Atrophy (etiology, therapy)
• Neuromuscular Junction (metabolism, pathology)
• Superoxide Dismutase (genetics, immunology)
• Synaptophysin (metabolism)