In amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, 
TAR DNA binding protein 43 (TDP-43) accumulates in the cytoplasm of affected 
neurons and glia, where it associates with stress granules (SGs) and forms large 
inclusions. SGs form in response to cellular stress, including endoplasmic 
reticulum (ER) stress, which is induced in both familial and sporadic forms of 
ALS. Here we demonstrate that pharmacological induction of ER stress causes 
TDP-43 to accumulate in the cytoplasm, where TDP-43 also associates with SGs. 
Furthermore, treatment with salubrinal, an inhibitor of dephosphorylation of 
eukaryotic initiation factor 2-α, a key modulator of ER stress, potentiates ER 
stress-mediated SG formation. Inclusions of C-terminal fragment TDP-43, 
reminiscent of disease-pathology, form in close association with ER and Golgi 
compartments, further indicating the involvement of ER dysfunction in 
TDP-43-associated disease. Consistent with this notion, over-expression of 
ALS-linked mutant TDP-43, and to a lesser extent wildtype TDP-43, triggers 
several ER stress pathways in neuroblastoma cells. Similarly, we found an 
interaction between the ER chaperone protein disulphide isomerase and TDP-43 in 
transfected cell lysates and in the spinal cords of mutant A315T TDP-43 
transgenic mice. This study provides evidence for ER stress as a pathogenic 
pathway in TDP-43-mediated disease.