Abstract

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 with motoneurons vulnerability in ALS. Protein disulfide isomerases (PDIs) are key enzymes catalyzing protein folding at the ER that are altered in the disease, involving biochemical and genetic perturbations. In ALS cases, we previously identified variants in the gene encoding PDIA3 (also known as Grp58 or ERp57), 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 ALSassociated PDIA3Q481K variant. Moderate PDIA3Q481K overexpression resulted in altered motor capacity accompanied by decreased motoneuron number. The adverse effects of PDIA3Q481K expression were associated with induction of ER stress in the spinal cord and subtle morphological changes in neuromuscular junctions. Our results suggest that the PDIA3Q481K variant is likely pathogenic and its overexpression in mice recapitulate some ALS features, further supporting the concept that altered proteostasis due to PDI dysfunction may predispose an individual to develop the disease.