Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases

Equilibrated protein homeostasis (referred to as proteostasis) requires the dynamic coordination of efficient folding of newly synthesized proteins, quality control and degradative mechanisms to reduce the load of unfolded and/or misfolded proteins and thereby prevent abnormal protein aggregation. In response to proteostasis perturbations, the folding and/or degrading capacity of the endoplasmic reticulum (ER) is dynamically adjusted by the induction of a complex signalling network known as the unfolded protein response (UPR).Most neurodegenerative diseases are considered to be protein misfolding disorders. They have distinct clinical manifestations, but they all involve the accumulation of abnormally folded proteins in the form of small oligomers, aggregates or large-protein inclusions. Disturbance of several aspects of proteostasis contributes to the progression of these neurodegenerative diseases.Perturbation of ER function or the UPR may be part of the aetiology of several diseases; that is, disease proteins may directly or indirectly perturb the UPR machinery and alter the function of the secretory pathway at different levels, resulting in irreversible alterations in neuronal proteostasis and degeneration.UPR activation can either enhance or reduce neurodegeneration. UPR adaptive responses or pro-apoptotic programmes are possibly triggered depending on the load of misfolded proteins and the specific UPR signalling mechanisms that are activated.An ER adaptive response can engage a preconditioning stage by adjusting proteostasis in neurons but can also propagate cell-non-autonomously in the whole organism to maintain global proteostasis and limit ageing. Physiological perturbation of the ER through the engagement of adaptive ER-hormetic mechanisms could be exploited to develop therapeutic strategies that attenuate neurodegeneration.UPR pathways have physiological functions in different aspects of brain development and function, such as CNS development, learning, memory and hypothalamic functions.