Abstract
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by a selective loss of motor neurons together with a progressive muscle weakness. Albeit the pathophysiological mechanisms of the disease remain unknown, growing evidence suggests that skeletal muscle can be a target of ALS toxicity. In particular, the two main intracellular degradation mechanisms, autophagy and the ubiquitin-proteasome degradative system (UPS) have been poorly studied in this tissue. In this study we investigated the activation of autophagy and the UPS as well as apoptosis in the skeletal muscle from SOD1G93A mice along disease progression. Our results showed a significant upregulation of proteasome activity at early symptomatic stage, while the autophagy activation was found at presymptomatic and terminal stages. The mRNA upregulated levels of LC3, p62, Beclin1, Atg5 and E2f1 were only observed at symptomatic and terminal stages, which reinforced the time-point activation of autophagy. Furthermore, no apoptosis activation was observed along disease progression. The combined data provided clear evidence for the first time that there is a time-point dependent activation of autophagy and UPS in the skeletal muscle from SOD1G93A mice.
Highlights
Autophagy and the ubiquitin-proteasome degradative system (UPS) are considered two main critical mechanisms that contribute to basal elimination of misfolded proteins and they maintain the balancing protein homeostasis inside cells
Activation of autophagy at presymptomatic and the late stages of the disease To characterize the autophagy machinery in SOD1G93A mice along disease progression, the mRNA levels of Lc3, p62, Beclin1, Atg5 and E2f1 genes were first quantified by real-time PCR in the skeletal muscle tissue of Wild type (WT) and SOD1G93A mice at P40, P60, P90 and P120
At early symptomatic stage (P60), mRNA levels of Beclin1 and Atg5 were significantly downregulated in SOD1G93A mice, while upregulated levels were found in the case of E2f1
Summary
Autophagy and the ubiquitin-proteasome degradative system (UPS) are considered two main critical mechanisms that contribute to basal elimination of misfolded proteins and they maintain the balancing protein homeostasis inside cells. Autophagy and UPS in SOD1G93A Mice an impairment in autophagy to the progression of ALS showed a significant upregulation of the activated microtubule-associated protein 1 light chain (LC3) protein levels at the end symptomatic stage in the spinal cord from SOD1G93A mice, one of the best characterized animal models of the disease[2, 3]. At this step, autophagy, an intracellular process that leads to the elimination of cytoplasmic components inside lysosomes, was proposed as the main process that degraded mutant SOD1 in vitro and in vivo in the spinal cord from SOD1G93A mice[4]. The UPS is an important mechanism for the degradation of misfolded proteins exporting from ER and its failure can lead to significant ER stress[7, 15,16,17]
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