Abstract
Amyotrophic lateral sclerosis (ALS) is a motoneuron disease characterized by misfolded proteins aggregation in affected motoneurons. In mutant SOD1 (mutSOD1) ALS models, aggregation correlates to impaired functions of proteasome and/or autophagy, both essential for the intracellular chaperone-mediated protein quality control (PQC), and to a reduced mutSOD1 clearance from motoneurons. Skeletal muscle cells are also sensitive to mutSOD1 toxicity, but no mutSOD1 aggregates are formed in these cells, that might better manage mutSOD1 than motoneurons. Thus, we analyzed in spinal cord and in muscle of transgenic (tg) G93A-SOD1 mice at presymptomatic (PS, 8 weeks) and symptomatic (S, 16 weeks) stages, and in age-matched control mice, whether mutSOD1 differentially modulates relevant PQC players, such as HSPB8, BAG3, and BAG1. Possible sex differences were also considered. No changes of HSPB8, BAG3, and BAG1 at PS stage (8 weeks) were seen in all tissues examined in tg G93A-SOD1 and control mice. At S stage (16 weeks), HSPB8 dramatically increased in skeletal muscle of tg G93A-SOD1 mice, while a minor increase occurred in spinal cord of male, but not female tg G93A-SOD1 mice. BAG3 expression increased both in muscle and spinal cord of tg G93A-SOD1 mice at S stage, BAG1 expression increased only in muscle of the same mice. Since, HSPB8-BAG3 complex assists mutSOD1 autophagic removal, we analyzed two well-known autophagic markers, LC3 and p62. Both LC3 and p62 mRNAs were significantly up-regulated in skeletal muscle of tg G93A-SOD1 mice at S stage (16 weeks). This suggests that mutSOD1 expression induces a robust autophagic response specifically in muscle. Together these results demonstrate that, in muscle mutSOD1-induced autophagic response is much higher than in spinal cord. In addition, if mutSOD1 exerts toxicity in muscle, this may not be mediated by misfolded proteins accumulation. It remains unclear whether in muscle mutSOD1 toxicity is related to aberrant autophagy activation.
Highlights
Autophagy is a fundamental intracellular degradative pathway activated to respond to the accumulation of aberrantly folded proteins (Mizushima and Komatsu, 2011)
Based on our data on the protective role of HSPB8 in amyotrophic lateral sclerosis (ALS), which is mediated by autophagy, we analyzed the expression of this small chaperone in the spinal cord and muscle of Tg G93ASOD1 mice and control mice
Using homogenates of spinal cord and skeletal muscle derived from Tg G93A-superoxide dismutase 1 (SOD1) mice and age-matched Non-transgenic littermates were used as controls (NTg) or Tg wtSOD1 mice, we first compared the levels of wtSOD1 and mutant SOD1 (mutSOD1) in both the soluble and insoluble fractions in 8 and 16 weeks male and female mice
Summary
Autophagy is a fundamental intracellular degradative pathway activated to respond to the accumulation of aberrantly folded (misfolded) proteins (Mizushima and Komatsu, 2011). Autophagy is required for the cellular protein quality control (PQC) system, which includes molecular chaperones and the ubiquitin-proteasome degradative system (UPS) (Carra et al, 2012) These systems work together protecting cells sensitive to misfolded protein toxicity, such as motoneurons (Rusmini et al, 2010; Bendotti et al, 2012; Carra et al, 2013). The wild type (wt) forms of the mutated fALS proteins may show aberrant behavior in sALS (e.g., oxydized wtSOD1, cleaved C-terminus of wtTDP-43, etc.) (Neumann et al, 2006; Daoud et al, 2009; Bosco and Landers, 2010; Bosco et al, 2010), suggesting the existence of a common pathological mechanism An explanation for this is that these proteins (either the modified wt or the mutant forms) have the propensity to misfold and aggregate forming
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