Abstract
Neurons are highly specialized cells that continuously and extensively communicate with other neurons, as well as glia cells. During their long lifetime, the post-mitotic neurons encounter many stressful situations that can disrupt protein homeostasis (proteostasis). The importance of tight protein quality control is illustrated by neurodegenerative disorders where disturbed neuronal proteostasis causes neuronal dysfunction and loss. For their unique function, neurons require regulated and long-distance transport of membrane-bound cargo and organelles. This highlights the importance of protein quality control in the neuronal endomembrane system, to which the unfolded protein response (UPR) is instrumental. The UPR is a highly conserved stress response that is present in all eukaryotes. However, recent studies demonstrate the existence of cell-type-specific aspects of the UPR, as well as cell non-autonomous UPR signaling. Here we discuss these novel insights in view of the complex cellular architecture of the brain and the implications for neurodegenerative diseases.
Highlights
Neurons have an elaborate endomembrane system that underlies their unique function
Different studies suggested that the activation of all three branches of the unfolded protein response (UPR) is transmissible from tumor cells in which ER stress was induced by using compounds to unstressed macrophages via conditioned media (CM) [70]
The non-conventional secretion triggered by the disruption of the conventional secretory pathway is probably mediated through ER stress and the UPR, since alternative ER-stress-inducing treatments induce unconventional secretion [89,94,167]. These results suggest that the UPR is involved in triggering unconventional secretion to bypass a block in the canonical secretory route, thereby preventing protein accumulation in the ER
Summary
Neurons have an elaborate endomembrane system that underlies their unique function. In order to maintain protein homeostasis (“proteostasis”) in the neuronal endomembrane system, an intricate network of protein quality control machinery is in place [1], in which the unfolded protein response (UPR) plays a central role (reviewed in Reference [2]).
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