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ALS ‐linked protein disulfide isomerase variants cause motor dysfunction

2016; Springer Nature; Volume: 35; Issue: 8 Linguagem: Inglês

10.15252/embj.201592224

1460-2075

Ute Woehlbier, Alicia Colombo, Mirva J. Saaranen, Viviana Pérez, Jorge Ojeda, Fernando J. Bustos, Catherine I. Andreu, Mauricio Torres, Vicente Valenzuela, Danilo B. Medinas, Pablo Rozas, René L. Vidal, Rodrigo López‐González, Johnny Salameh, Sara Fernández‐Collemann, Natalia Albornoz, Soledad Matus, Ricardo Armisén, Alfredo Sagredo, Karina Palma, Thergiory Irrazábal, Sandra Almeida, Paloma González-Pérez, Mario Campero, Fen‐Biao Gao, Pablo Henny, Brigitte van Zundert, Lloyd W. Ruddock, Miguel L. Concha, Juan Pablo Henríquez, Robert H. Brown, Claudio Hetz,

Neurogenetic and Muscular Disorders Research

Abstract Disturbance of endoplasmic reticulum ( ER ) proteostasis is a common feature of amyotrophic lateral sclerosis ( ALS ). Protein disulfide isomerases ( PDI s) 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, PDIA 1 and PDIA 3/ ER p57. 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 PDI s 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 ER p57 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.