In models of HD, mutant huntingtin can also alter the trafficking through the secretory pathway at different levels. In the case of ALS, several mutations have been identified that are predicted to generate disturbances in ER proteostasis, including intronic variants of PDI, or mutations in genes involved in protein degradation such as UBQLN. For example, mutant VAPB interacts with ATF, inhibiting its transcriptional activity. Similarly, a correlative study suggested that expression of mutant huntingtin triggers the selective inhibition of ATF but not other UPR branches.Many ER chaperones and foldases require the direct binding of calcium to maintain optimal activity, which is perturbed by conditions that trigger ER calcium depletion.There is a vast literature depicting abnormal release of calcium from the ER in several pathological conditions affecting the nervous system. All rights reserved R E V I E W S receptor, which altered ER calcium homeostasis. Similarly, inhibition of the ryanodine receptor in a mouse model of HD provided significant neuroprotection.In the context of PD, an interesting mechanism was recently proposed to affect ER calcium homeostasis.Additional studies have shown that UPR signalling interferes with the early steps of APP maturation and processing. ATF can also regulate the expression of presenilins and can affect the activity of secretases. In summary, all of the examples provided in this section depict distinct molecular mechanisms that may alter the function of the secretory pathway at different levels and converge to cause the irreversible alteration of ER proteostasis and neurodegeneration.This idea has been reinforced through the use of the concept of hormesis, which involves the engagement of a preconditioning state via mild, nonlethal stress to induce adaptive reactions and protect the cell from a second, stronger injury. In medicine, quick cycles of ischaemic preconditioning prepare the heart before surgery. In genetic and toxinbased models of PD, pretreatment with nontoxic doses of the ER stressinducing agent tunicamycin protects against degeneration involving the selective activation of IREXBP but not ATFCHOP pathways.This protective effect was also associated with the upregulation of autophagy.Despite this, there is very little information available about basal levels of UPR activity in the nervous system, and this information is crucial to predict possible side effects of targeting the UPR using small molecules or gene therapy.In this section, we discuss the few studies that have suggested a physiological role for the UPR in different aspects of brain function.The integrated stress response in learning and memory.Translational control through the phosphorylation of eIF and the expression of ATF have been shown to be involved in the process of memory consolidation.Genetic and pharmacological evidence indicates that phosphorylat ion of eIF has inhibitoryactiv ity in longterm potentiation and memory consolidation. In obese patients, free fatty acids and other metabolites could induce ER stress in the hypothalamus, which in turn inactivates leptindependent control of appetite and energy consumption by the organism.These events might be inhibited by active, spliced XBP. During ageing, there is a progressive loss of ER proteostasis, which causes an attenuation of stress responses.In the context of ageing, there is activation of xbp mRNA splicing and subsequent translation, and activation of target genes that trigger the synthesis of diffusible unknown signalling molecules termed secreted ER stressinducing signals, which there is some evidence to suggest are transported as membranebound cargo to the axon terminal and released.