Protein disulfide isomerase ERp57 protects early muscle denervation in experimental ALS
Author
dc.contributor.author
Rozas Rojas, Pablo Sebastián
Author
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Pinto, Cristina
Author
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Martínez Traub, Francisca José
Author
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Díaz Hinojosa, Rodrigo Ignacio
Author
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Pérez, Viviana
Author
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Becerra, Daniela
Author
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Ojeda, Patricia
Author
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Ojeda, Jorge
Author
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Wright, Madison T.
Author
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Mella, Jéssica
Author
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Plate, Lars
Author
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Henríquez, Juan Pablo
Author
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Hetz Flores, Claudio Andrés
Author
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Bilches Medinas, Danilo
Admission date
dc.date.accessioned
2021-12-09T12:04:51Z
Available date
dc.date.available
2021-12-09T12:04:51Z
Publication date
dc.date.issued
2021
Cita de ítem
dc.identifier.citation
Acta neuropathol commun (2021) 9:21
es_ES
Identifier
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10.1186/s40478-020-01116-z
Identifier
dc.identifier.uri
https://repositorio.uchile.cl/handle/2250/183121
Abstract
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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.
es_ES
Patrocinador
dc.description.sponsorship
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
es_ES
Lenguage
dc.language.iso
en
es_ES
Publisher
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BMC
es_ES
Type of license
dc.rights
Attribution-NonCommercial-NoDerivs 3.0 United States