ALS-linked protein disulfide isomerase variants cause motor dysfunction

• Published in: The EMBO journal 2016-04, Vol.35 (8), p.845-865
• Main Authors: Woehlbier, Ute, Colombo, Alicia, Saaranen, Mirva J, Pérez, Viviana, Ojeda, Jorge, Bustos, Fernando J, Andreu, Catherine I, Torres, Mauricio, Valenzuela, Vicente, Medinas, Danilo B, Rozas, Pablo, Vidal, Rene L, Lopez-Gonzalez, Rodrigo, Salameh, Johnny, Fernandez-Collemann, Sara, Muñoz, Natalia, Matus, Soledad, Armisen, Ricardo, Sagredo, Alfredo, Palma, Karina, Irrazabal, Thergiory, Almeida, Sandra, Gonzalez-Perez, Paloma, Campero, Mario, Gao, Fen-Biao, Henny, Pablo, van Zundert, Brigitte, Ruddock, Lloyd W, Concha, Miguel L, Henriquez, Juan P, Brown, Robert H, Hetz, Claudio
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Animals; Animals, Genetically Modified; Electromyography; EMBO24; EMBO27; Embryo, Nonmammalian; Endoplasmic reticulum; Endoplasmic Reticulum Stress - genetics; ERp57; Humans; Mice, Knockout; Motor Neurons - pathology; Mutants; Mutation; Neurites - pathology; Pathogens; PDIA1; Procollagen-Proline Dioxygenase - genetics; Procollagen-Proline Dioxygenase - metabolism; protein disulfide isomerase; Protein Disulfide-Isomerases - genetics; Protein Disulfide-Isomerases - metabolism; Proteins; Risk factors; Zebrafish - embryology; Zebrafish - genetics
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.15252/embj.201592224

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. Synopsis The degeneration of motoneurons in ALS is associated with a chronic endoplasmic reticulum (ER) stress response. Here we report the consequences of mutations of two major ER foldases in ALS known as PDIA1 and ERp57. Expression of these ALS‐linked mutants trigger some cardinal features of ALS, including the disruption of motoneuron connectivity and function, highlighting ER proteostasis imbalance as a driver of the initial stages of the disease. ALS‐linked mutations in PDIA1 and ERp57 adversely affect PDI structure and function. PDI mutants cause abnormal motoneuron morphology and functionality. Targeting of ERp57 in the CNS results in premature death and impaired motor control. ERp57 deficiency causes alterations of neuromuscular junctions. Graphical Abstract Disease phenotypes associated with expression of mutant PDIA1 and ERp57 show how impaired ER proteostasis can drive initial stages of amyotrophic lateral sclerosis pathology.