Woehlbier, UteColombo, AliciaSaaranen, MirvaPérez, VivianaOjeda, JorgeBustos, FernandoAndreu, CatherineTorres, mauricioValenzuela, VicenteMedinas, DaniloRozas, PabloVidal, RenéLópez-González, RodrigoSalameh, JohnnyFernández-Collemann, SaraMuñoz, NataliaMatus, SoledadArmisén, RicardoSagredo, AlfredoPalma, KarinaIrrazabal, ThergioryAlmeida, SandraGonzález-Pérez, PalomaCampero, Mario2017-01-042017-01-042016Woehlbier U, Colombo A, Saaranen MJ, Pérez V, Ojeda J, Bustos FJ, Andreu CI, Torres M, Valenzuela V, Medinas DB, Rozas P, Vidal RL, Lopez-Gonzalez R, Salameh J, Fernandez-Collemann S, Muñoz N, Matus S, Armisen R, Sagredo A, Palma K, Irrazabal T, Almeida S, Gonzalez-Perez P, Campero M, Gao FB, Henny P, van Zundert B, Ruddock LW, Concha ML, Henriquez JP, Brown RH, Hetz C. ALS-linked protein disulfide isomerase variants cause motor dysfunction. EMBO J. 2016 Apr 15;35(8):845-65.http://hdl.handle.net/11447/925http://dx.doi.org/ 10.15252/embj.201592224Disturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) areERfoldases identified as possibleALSbiomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized fourALS-linked mutations recently identified in two majorPDIgenes,PDIA1 andPDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of thesePDIvariants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutantPDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of thesePDImutants. Finally, targetingERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifiesERproteostasis imbalance as a risk factor forALS, driving initial stages of the disease.en-USERp57PDIA1Amyotrophic lateral sclerosisProtein disulfide isomeraseArtículo