Most neurodegenerative diseases share a common neuropathology, primarily featuring the presence of abnormal protein inclusions containing specific misfolded proteins. Recent evidence indicates that alteration in organelle function is a common pathological feature of protein misfolding disorders. The endoplasmic reticulum (ER) is an essential compartment for protein folding, maturation, and secretion. Signs of ER stress have been extensively described in most experimentalmodels of neurological disorders. To cope with ER stress, cells activate an integrated signaling response termed the Unfolded Protein Response (UPR), which aims to reestablish homeostasis through transcriptional upregulation of genes involved in protein folding, quality control and degradation pathways. Here we discuss our efforts to assess the role of the UPR in brain diseases, and develop gene therapy strategies to alleviate ER stress in specific brain regions. Examples in ALS, Alzheimer´s disease and Parkinson´s disease will be provided. A new concept is emerging where depending on specific UPR component targeted and the disease model tested distinct and even opposite effects can be observed on the pathology.