Several reports have shown that chronic ER stress partly mediates the loss of oligodendrocytes in experimental models of multiple sclerosis.For example, early studies showed that in various multiple sclerosis models, activation of PERK contributes to oligodendrocyte survival and remyelination. Remarkably, an elegant study recently demonstrated that persistent artificial activation of PERK in oligodendrocytes does not trigger apoptosis, attenuates the development of experimental multiple sclerosis and is associated with improved remyelination, oligodendrocyte survival and axonal degeneration.ER stress has also been linked to oligodendrocyte survival in other myelinrelated disorders.Recent evidence indicates that the UPR has an important role in finetuning cholesterol and lipid metabolism in the body. Lysosomal storage disorders are a group of fatal neurodegenerative and hereditary conditions associated with lysosomal dysfunction.Similarly, GM gangliosidosis and infantile neuronal ceroid lipofuscinoses involve abnormal sphingolipid metabolism.These lysosomal storage disorders have been shown to be associated with the occurrence of chronic ER stress in several studies.However, functional data linking cholesterol and sphingolipid alterations to the UPR in the brain are still lacking, and this topic remains an interesting area for future research.As the examples discussed above make clear, there has been an explosion of functional studies in recent years that validate the UPR signalling network as a relevant target for future therapeutic strategies. However, the cellular responses triggered by this pathological perturbation can vary depending on the nature of the protein affected and its subcellular distribution.Indeed, a number of groundbreaking studies demonstrated that ER stress is a crucial component underlying neuronal loss in cellular models of AD.It is also important to highlight the fact that only few examples indicate a direct alteration of ER function by diseaserelated proteins.A few examples have shown that mutations in neurodegenerative diseases affect proteins that are synthesized through the secretory pathway, leading to their retention in the ER lumen and their degradation by the ERAD pathway.The accumulation of these mutant proteins in the ER triggers a chronic ER stress response, but as ment ioned above, there is no ev idence so far that they engage the activation of UPR stress sensors directly as a dangersignal.Mutant fused in sarcoma also associates with PDI.These interactions may result in the sequestration of these chaperones, ablating their function.Mutant vesicleassociated membrane proteinassociated protein B, both of which are required for trafficking.This led the authors to speculate that synuclein oligomers may sequester components of the ER folding Cefadroxil machinery, triggering a chronic disturbance of ER proteostasis. Similar Fluorescein observations have been reported for mutant SOD in ALS models.Simi larly, mutant FUS and TDP were recently reported to associate with PDI in cell culture models and ALS human postmortem tissue. Functional studies in cellcu lture models suggest that these ER chaperones may actually reduce protein aggregation and increase neuronal viability, possibly owing to a reduction of general ER stress. In addition, direct inactivation of PDI through oxidative modification, which may ablate the neuroprotective activity of this foldase, has been suggested in models of PD, AD and ALS.For example, mutant SOD and huntingtin have been shown to target the ERAD machinery, leading to ERAD impairment and pathological ER stress.

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