Emerging Roles for the Unfolded Protein Response in the Developing Nervous System

Abstract

The unfolded protein response (UPR) is a homeostatic signaling pathway triggered by protein misfolding in the endoplasmic reticulum (ER). Beyond its protective role, it plays important functions during normal development in response to elevated demand for protein folding. Several UPR effectors show dynamic temporal and spatial expression patterns that correlate with milestones of the central nervous system (CNS) development. Here, we discuss recent studies suggesting that a dynamic regulation of UPR supports generation, maturation, and maintenance of differentiated neurons in the CNS. We further highlight studies supporting a developmental vulnerability of CNS to UPR dysregulation, which underlies neurodevelopmental disorders. We believe that a better understanding of UPR functions may provide novel opportunities for therapeutic strategies to fight ER/UPR-associated human neurological disorders.

MANF Is Essential for Neurite Extension and Neuronal Migration in the Developing Cortex

“…Previous studies have indicated that MANF is upregulated in ER stress conditions in vitro ( Apostolou et al, 2008 ; Glembotski et al, 2012 ) and lack of MANF leads to chronic UPR activation in pancreatic islets in vivo ( Lindahl et al, 2014 ). It has also been shown that dysregulation of UPR can cause defects in neurogenesis and neuronal maturation and that these mechanisms could underlie neurodevelopmental disorders ( Godin et al, 2016 ). Therefore, we wanted to investigate whether increased ER stress and activated UPR also appear in Manf -/- NSCs and measured the expression levels of UPR genes Grp78, Atf4, Atf6a, spliced Xbp1, and Chop, which are known to increase under ER stress conditions.…”

Olfactory receptor accessory proteins play crucial roles in receptor function and gene choice

“…Previous studies have shown that the unfolded protein response (UPR) plays an important role in OR gene choice mechanisms. During the initial phase of OR expression, the UPR pathway gives rise to an increased translation of nuclear activating transcription factor (nATF5) over an upstream inhibitory ORF via eIF2α signaling (Godin et al, 2016). Once the OSN has matured, OR gene choice is stabilized and the UPR is relieved (Dalton et al, 2013).…”

Enzymes Involved in AMPylation and deAMPylation

“…This could be especially critical in cell types that require sensitive UPR responses such as neurons and supporting cells. 82 …”