The role of amyloid β in the pathological mechanism of GNE myopathy

Abstract

GNE myopathy is a hereditary muscle disorder characterized by muscle atrophy and weakness initially involving the lower distal extremities. The treatment of GNE myopathy mainly focuses on a sialic acid deficiency caused by a mutation in the GNE gene, but it has not achieved the expected effect. The main pathological features of GNE myopathy are myofiber atrophy and rimmed vacuoles, including accumulation of amyloid β, which is mainly found in atrophic muscle fibers. Although the role of amyloid β and other misfolded proteins on the nervous system has been widely recognized, the cause and process of the formation of amyloid β in the pathological process of GNE myopathy are unclear. In addition, amyloid β has been reported to be linked to quality control mechanisms of proteins, such as molecular chaperones, the ubiquitin-proteasome system, and the autophagy-lysosome system. Herein, we summarize the possible reasons for amyloid β deposition and illustrate amyloid β-mediated events in the cells and their role in muscle atrophy in GNE myopathy. This review represents an overview of amyloid β and GNE myopathy that could help identify a potential mechanism and thereby a plausible therapeutic for the disease.

Keywords: Amyloid β; Autophagy; GNE myopathy; Mitophagy; Muscle atrophy; Sialic acid.

Fig. 1

Molecular events present in GNE myopathy. Abnormal GM3 and GD3 lead to Aβ synthesis disorder in the Golgi apparatus and endoplasmic reticulum of GNE. At the same time, hyposialylated NEP cannot clear Aβ. Aβ deposition generates ER stress in GNE-mutant cells, which further triggers survival or apoptotic signaling mediated by IRE1-α or PERK, respectively. Molecular chaperones, ERAD, and UPS are all involved in the clearance of misfolded proteins. In the case of Aβ deposition, the autophagy-lysosome pathway is activated immediately to correct or degrade Aβ. Many molecules related to apoptosis in GNE myopathy, such as caspase 3, caspase 9, and IGF-1R, control cell survival and apoptosis by regulating the balance between AKT and ERK

Fig. 2

Molecular mechanisms of skeletal muscle atrophy. Mutations in the GNE gene lead to excessive ROS production after muscle contraction. At the same time, Aβ deposition also causes oxidative stress. Skeletal muscle mitochondria are disturbed and atrogenes are upregulated. GNE can interact with α-actinin and activate RhoA. Phosphorylation of cofilin hampers F-actin depolymerization and the generation of G-actin monomers. GNE gene mutation leads to cytoskeletal disruption and slowed cell migration. Consequently, muscle atrophy may occur