The effect of GPNMB on muscular atrophy caused by ALS

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating disease characterized by the degeneration of motor neurons and subsequent muscular defects. Recent findings have highlighted the contribution of intrinsic skeletal muscle defects to ALS. Research focusing on skeletal muscle disorders might therefore offer alternative routes to the development of new therapeutic options for the treatment of ALS. Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transmembrane protein also known as osteoactivin (OA) and dendritic cell-heparin integrin ligand (DC-HIL). GPNMB exerts a protective effect on the central nervous system, and it has been shown to improve memory and to help recovery from reperfusion injury following brain ischemia. In ALS model mice, overexpression of GPNMB prevents motor neuron death and reduces denervation of neuromuscular junctions and atrophy of the skeletal muscles, resulting in a delayed onset of ALS and a longer life span of the animals. When directly injected into skeletal muscle, GPNMB also helps prevent injury of myofibers. These data indicate that GPNMB has a dual site of action against the central nervous system and directly skeletal muscle. Here, we review and highlight recent findings on the effect of GPNMB against ALS, and we discuss remaining challenges of the field and the possible therapeutic applications of GPNMB.