ERN1 and neurodegenerative disease: For example, prolonged ER stress in neurodegenerative diseases leads to activation of UPR signalling, triggering a set of pro-death programs (27); however, it has been seen that XBP1 generation through splicing (involved in IRE1 signalling) is dispensable in the process and does not contribute to the neurodegeneration associated with prion protein misfolding (28).