Protein disulfide isomerase ERp57 protects early muscle denervation in experimental ALS
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2021Metadata
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Rozas Rojas, Pablo Sebastián
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Protein disulfide isomerase ERp57 protects early muscle denervation in experimental ALS
Author
- Rozas Rojas, Pablo Sebastián;
- Pinto, Cristina;
- Martínez Traub, Francisca José;
- Díaz Hinojosa, Rodrigo Ignacio;
- Pérez, Viviana;
- Becerra, Daniela;
- Ojeda, Patricia;
- Ojeda, Jorge;
- Wright, Madison T.;
- Mella, Jéssica;
- Plate, Lars;
- Henríquez, Juan Pablo;
- Hetz Flores, Claudio Andrés;
- Bilches Medinas, Danilo;
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 SOD1(G93A)/ERp57(WT) animals presented delayed deterioration of electrophysiological activity and maintained muscle innervation compared to single transgenic SOD1(G93A) 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.
Patrocinador
Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)
CONICYT FONDECYT 1140549
15150012
11150579
1191538
3190255
1170614
Muscular Dystrophy Association 382453
575897
ALS Association 19-IIA-456
ANID/FONDAP 15150012
Takeda Pharmaceutical Company Ltd P09-015-F
FONDEF ID16I10223
ID11E1007
CONICYT-Brazil 441921/2016-7
Michael J Fox Foundation for Parkinson's Research-Target Validation grant 9277
European Commission RD MSCA-RISE 734749
United States Department of Defense 81XWH-16-1-0112
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Artículo de publícación WoS
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Acta neuropathol commun (2021) 9:21
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