Protein folding stress is a salient pathological feature of sporadic and familial amyotrophic lateral sclerosis (ALS). The presence of TAR DNA binding protein 43 kDa (TDP-43) was described as the main constituent of protein aggregates in ALS and Fronto Temporal Dementia (DFT). Familial mutations in TDP-43 trigger its mislocalization from the nucleus to the cytosol, and its abnormal aggregation in the cysotosol. The overexpression of ALS-linked mutant TDP-43 in transgenic mice recapitulates essential features of the human pathology provoking age-dependent paralysis and neuronal degeneration. The primary mechanism by which mutations in TDP-43 contribute to progressive motor neuron loss in ALS remains unknown. Interestingly, several studies indicate that ALS progression directly correlates with a strong stress response at the endoplasmic reticulum (ER), an essential compartment involved in protein folding and quality control mechanisms. We have found that different DTT sensitive high molecular species of TDP-43 are selectively present in tissues affected in the mutant TDP-43 ALS mouse model, including spinal cord and motor cortex. Unexpectedly, we have found that the stress responses coming form the ER are impaired in mouse and cellular models expressing mutant forms of TDP-43. These data shows that mutant forms of TDP-43 could be involved in the insensibility of mutant TDP-43 systems to respond under ER or other stress conditions.