Protein disulfide isomerase ERp57 protects early muscle denervation in experimental ALS

Acta Neuropathologica Communications

Danilo B. Medinas¹  Pablo Rozas¹  Francisca Martínez Traub¹  Daniela Becerra¹  Claudio Hetz¹  Patricia Ojeda¹  Rodrigo Díaz¹  Lars Plate²  Madison T. Wright²  Jessica Mella³  Juan Pablo Henríquez³  Jorge Ojeda³  Cristina Pinto³  Viviana Pérez³ 

[1]Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile

[2]Department of Chemistry and Department of Biological Sciences, Vanderbilt University

[3]Neuromuscular Studies Laboratory (NeSt Lab), Department of Cell Biology, Faculty of Biological Sciences, Center for Advanced Microscopy (CMA Bio-Bio), Universidad de Concepción

关键词: Amyotrophic lateral sclerosis;    Mutant SOD1;    ERp57;    Protein aggregation;    Neuromuscular junction;   

DOI  :  10.1186/s40478-020-01116-z

来源: DOAJ

【 摘 要 】

Abstract Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease that affects motoneurons. Mutations in superoxide dismutase 1 (SOD1) have been described as a causative genetic factor for ALS. Mice overexpressing ALS-linked mutant SOD1 develop ALS symptoms accompanied by histopathological alterations and protein aggregation. The protein disulfide isomerase family member ERp57 is one of the main up-regulated proteins in tissue of ALS patients and mutant SOD1 mice, whereas point mutations in ERp57 were described as possible risk factors to develop the disease. ERp57 catalyzes disulfide bond formation and isomerization in the endoplasmic reticulum (ER), constituting a central component of protein quality control mechanisms. However, the actual contribution of ERp57 to ALS pathogenesis remained to be defined. Here, we studied the consequences of overexpressing ERp57 in experimental ALS using mutant SOD1 mice. Double transgenic SOD1G93A/ERp57WT animals presented delayed deterioration of electrophysiological activity and maintained muscle innervation compared to single transgenic SOD1G93A littermates at early-symptomatic stage, along with improved motor performance without affecting survival. The overexpression of ERp57 reduced mutant SOD1 aggregation, but only at disease end-stage, dissociating its role as an anti-aggregation factor from the protection of neuromuscular junctions. Instead, proteomic analysis revealed that the neuroprotective effects of ERp57 overexpression correlated with increased levels of synaptic and actin cytoskeleton proteins in the spinal cord. Taken together, our results suggest that ERp57 operates as a disease modifier at early stages by maintaining motoneuron connectivity.

【 授权许可】

Unknown