Amyotrophic lateral sclerosis, Alzheimer’s Disease, Parkinson’s Disease, Prion-related
Disorders, Huntington’s Disease and several other neurodegenerative disorders 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 experimental models of neurological disorders and more recently in the brains of human
patients affected with neurodegenerative conditions. ER stress is caused by functional disturbances, which
result in the accumulation of unfolded/misfolded proteins at the ER lumen. 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. Small molecules with chaperone-like activity have been shown to
alleviate ER stress and decrease protein misfolding in experimental disease settings. In this chapter we
overview the role of ER stress in pathological conditions such as protein misfolding disorders and spinal
cord injury, and discuss possible pharmacological strategies to target the UPR with therapeutic benefits.
