Expression of a protein disulfide isomerase A3 variant associated to amyotrophic lateral sclerosis triggers disease features in mice

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motoneurons and compromised proteostasis. Dysfunction of the endoplasmic reticulum (ER) has been identified as a transversal pathogenic mechanism associated to motoneurons vulnerability in ALS. Protein disulfide isomerases (PDIs) are key enzymes catalyzing protein folding at the ER that are altered in the disease, involving both biochemical and genetic perturbations. We previously identified mutations in the gene encoding PDIA3 (also known as Grp58 or ERp57) in ALS cases, which were associated with altered neurite outgrowth in cell culture and abnormal motoneuron connectivity in zebrafish. Here we report the generation of transgenic mice expressing the ALS-associated PDIA3Q481K variant. Moderate PDIA3Q481K overexpression resulted in altered motor capacity accompanied by decreased motoneurons number and induction of ER stress in the spinal cord. The adverse effects of PDIA3Q481K were associated with altered electromyogram without evident morphological changes in neuromuscular junctions. Our results suggest that the PDIA3Q481K variant is pathogenic and its overexpression in mice recapitulate some ALS features, further supporting the concept that altered proteostasis due to PDI dysfunction constitute a risk factor to develop the disease.