ALS-linked protein disulfide isomerase variants cause motor dysfunction
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Archivos
Fecha
2016-04
Profesor/a Guía
Facultad/escuela
Idioma
en
Título de la revista
ISSN de la revista
Título del volumen
Editor
EMBO Journal. Volume 35, Issue 8, Pages 845 - 865. 15 April 2016
Nombre de Curso
Licencia CC
Licencia CC
Resumen
Disturbance of endoplasmic reticulum (ER) proteostasis is a
common feature of amyotrophic lateral sclerosis (ALS). Protein
disulfide isomerases (PDIs) are ER foldases identified as possible
ALS biomarkers, as well as neuroprotective factors. However, no
functional studies have addressed their impact on the disease
process. Here, we functionally characterized four ALS-linked
mutations recently identified in two major PDI genes, PDIA1 and
PDIA3/ERp57. Phenotypic screening in zebrafish revealed that the
expression of these PDI variants induce motor defects associated
with a disruption of motoneuron connectivity. Similarly, the
expression of mutant PDIs impaired dendritic outgrowth in
motoneuron cell culture models. Cellular and biochemical studies
identified distinct molecular defects underlying the pathogenicity
of these PDI mutants. Finally, targeting ERp57 in the nervous
system led to severe motor dysfunction in mice associated with
a loss of neuromuscular synapses. This study identifies ER
proteostasis imbalance as a risk factor for ALS, driving initial
stages of the disease.
Notas
Indexación: Scopus.
Palabras clave
Amyotrophic Lateral Sclerosis, ERp57, PDIA1, Protein Disulfide Isomerase
Citación
Wiley-VCH Verlag