Endoplasmic reticulum stress leads to accumulation of wild-type SOD1 aggregates associated with sporadic amyotrophic lateral sclerosis

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Abstract

The identification of aberrant SOD1 WT species accumulating in the spinal cord during aging could reveal pathogenic species involved in sporadic (s)ALS. Using a combination of biochemical approaches, we discovered that disulfide–cross-linked SOD1 WT aggregates rise before other abnormal protein species during aging and are significantly increased in sALS spinal cord tissue. We also found that endoplasmic reticulum stress stimulates accumulation of these species, with involvement of tryptophan-32 oxidation. These results establish a connection between SOD1 WT aggregation and a major proteostasis network affected in ALS. Abnormal modifications to mutant superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (fALS). Misfolding of wild-type SOD1 (SOD1 WT) is also observed in postmortem tissue of a subset of sporadic ALS (sALS) cases, but cellular and molecular mechanisms generating abnormal SOD1 WT species are unknown. We analyzed aberrant human SOD1 WT species over the lifetime of transgenic mice and found the accumulation of disulfide–cross-linked high–molecular-weight SOD1 WT aggregates during aging. Subcellular fractionation of spinal cord tissue and protein overexpression in NSC-34 motoneuron-like cells revealed that endoplasmic reticulum (ER) localization favors oxidation and disulfide-dependent aggregation of SOD1 WT. We established a pharmacological paradigm of chronic ER stress in vivo, which recapitulated SOD1 WTaggregation in young transgenic mice. These species were soluble in nondenaturing detergents and did not react with a SOD1 conformation-specific antibody. Interestingly, SOD1 WT aggregation under ER stress correlated with astrocyte activation in the spinal cord of transgenic mice. Finally, the disulfide–cross-linked SOD1 WT species were also found augmented in spinal cord tissue of sALS patients, correlating with the presence of ER stress markers. Overall, this study suggests that ER stress increases the susceptibility of SOD1 WT to aggregate during aging, operating as a possible risk factor for developing ALS.

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Most cited references 24

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ER stress and the unfolded protein response in neurodegeneration

Claudio Hetz, Smita Saxena (2017)

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A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice.

Smita Saxena, Erik Cabuy, Pico Caroni (2009)

The mechanisms underlying disease manifestations in neurodegeneration remain unclear, but their understanding is critical to devising effective therapies. We carry out a longitudinal analysis in vivo of identified motoneurons selectively vulnerable (VUL) or resistant (RES) to motoneuron disease (amyotrophic lateral sclerosis, ALS) and show that subtype-selective endoplasmic reticulum (ER) stress responses influence disease manifestations. VUL motoneurons were selectively prone to ER stress and showed gradually upregulated ER stress markers from birth on in three mouse models of familial ALS (FALS). 25-30 days before the earliest denervations, ubiquitin signals increased in both VUL and RES motoneurons, but an unfolded protein response coupled with microglial activation was initiated selectively in VUL motoneurons. This transition was followed by selective axonal degeneration and spreading stress. The ER stress-protective agent salubrinal attenuated disease manifestations and delayed progression, whereas chronic enhancement of ER stress promoted disease. Thus, whereas all motoneurons are preferentially affected in ALS, ER stress responses in specific motoneuron subtypes influence the progressive manifestations of weakening and paralysis.

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Protein disulfide isomerase: a critical evaluation of its function in disulfide bond formation.

Feras Hatahet, Lloyd W. Ruddock (2009)

Disulfide bond formation is probably involved in the biogenesis of approximately one third of human proteins. A central player in this essential process is protein disulfide isomerase or PDI. PDI was the first protein-folding catalyst reported. However, despite more than four decades of study, we still do not understand much about its physiological mechanisms of action. This review examines the published literature with a critical eye. This review aims to (a) provide background on the chemistry of disulfide bond formation and rearrangement, including the concept of reduction potential, before examining the structure of PDI; (b) detail the thiol-disulfide exchange reactions that are catalyzed by PDI in vitro, including a critical examination of the assays used to determine them; (c) examine oxidation and reduction of PDI in vivo, including not only the role of ERo1 but also an extensive assessment of the role of glutathione, as well as other systems, such as peroxide, dehydroascorbate, and a discussion of vitamin K-based systems; (d) consider the in vivo reactions of PDI and the determination and implications of the redox state of PDI in vivo; and (e) discuss other human and yeast PDI-family members.