Abstract
Although intracellular beta amyloid (Aβ) accumulation is known as an early upstream event in the degenerative course of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) myopathy, the process by which Aβdeposits initiate various degradative pathways, and their relationship have not been fully clarified. We studied the possible secondary responses after amyloid beta precursor protein (AβPP) deposition including unfolded protein response (UPR), ubiquitin proteasome system (UPS) activation and its correlation with autophagy system. Eight GNE myopathy patients and five individuals with normal muscle morphology were included in this study. We performed immunofluorescence and immunoblotting to investigate the expression of AβPP, phosphorylated tau (p-tau) and endoplasmic reticulum molecular chaperones. Proteasome activities were measured by cleavage of fluorogenic substrates. The expression of proteasome subunits and linkers between proteasomal and autophagy systems were also evaluated by immunoblotting and relative quantitative real-time RT-PCR. Four molecular chaperones, glucose-regulated protein 94 (GRP94), glucose-regulated protein 78 (GRP78), calreticulin and calnexin and valosin containing protein (VCP) were highly expressed in GNE myopathy. 20S proteasome subunits, three main proteasome proteolytic activities, and the factors linking UPS and autophagy system were also increased. Our study suggests that AβPP deposition results in endoplasmic reticulum stress (ERS) and highly expressed VCP deliver unfolded proteins from endoplasmic reticulum to proteosomal system which is activated in endoplasmic reticulum associated degradation (ERAD) in GNE myopathy. Excessive ubiquitinated unfolded proteins are exported by proteins that connect UPS and autophagy to autophagy system, which is activated as an alternative pathway for degradation.
Highlights
Distal myopathy with rimmed vacuoles (DMRV) or GNE myopathy is an autosomal recessive disorder clinically characterized by adult-onset of muscle weakness starting from distal muscles of legs and slowly progressing to proximal musculature with relative quadriceps sparing [1,2]
GNE myopathy is a degenerative myopathy in which rimmed vacuole formation induces muscle fiber atrophy and loss
They cause decreased GNE enzymatic activities resulting in decreased production of sialic acid, which leads to the muscle degeneration that is characterized by rimmed vacuole formation and intranuclear filamentous inclusions in GNE myopathy
Summary
Distal myopathy with rimmed vacuoles (DMRV) or GNE myopathy is an autosomal recessive disorder clinically characterized by adult-onset of muscle weakness starting from distal muscles of legs and slowly progressing to proximal musculature with relative quadriceps sparing [1,2]. Excellent experimental works have been done in pursuit of the supportive evidence for the hypothesis that it is the decrease in intracellular sialic acid content that leads to the muscle degeneration in GNE myopathy, the exact cellular mechanisms behind the development of the myopathy have remained elusive [8,9,10]. Intracellular Ab deposition in myofibers was rare and only documented in a few muscle diseases, such as sporadic inclusion body myositis (sIBM) and GNE myopathy [11]. Pathological features of GNE myopathy are very similar to those of sIBM Both have similar intracellular deposits that are congophilic and immunoreactive to AbPP, Ab, p-tau and other proteins related to ERS. In this study we investigated the deposition of AbPP and the secondary responses in GNE myopathy such as ERS and proteosomal activation. We studied the linkers between UPS and autophagy system and tried to find clues to the pathophysiology of GNE myopathy
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