The regulatory role of endoplasmic reticulum chaperone proteins in neurodevelopment

Abstract

The endoplasmic reticulum (ER) is the largest tubular reticular organelle spanning the cell. As the main site of protein synthesis, Ca²⁺ homeostasis maintenance and lipid metabolism, the ER plays a variety of essential roles in eukaryotic cells, with ER molecular chaperones participate in all these processes. In recent years, it has been reported that the abnormal expression of ER chaperones often leads to a variety of neurodevelopmental disorders (NDDs), including abnormal neuronal migration, neuronal morphogenesis, and synaptic function. Neuronal development is a complex and precisely regulated process. Currently, the mechanism by which neural development is regulated at the ER level remains under investigation. Therefore, in this work, we reviewed the recent advances in the roles of ER chaperones in neural development and developmental disorders caused by the deficiency of these molecular chaperones.

Keywords: endoplasmic reticulum; molecular chaperone; neurodevelopment; neuronal migration; neuronal morphogenesis; synaptic function.

FIGURE 1

Endoplasmic reticulum (ER) molecular chaperones involved in neurodevelopment. ER molecular chaperones regulate central nervous development through two mechanisms: 1. ER chaperones directly act on specific developmental periods and regulate developmental stages. 2. ER chaperones indirectly act on secretory proteins or receptor proteins and regulate ER stress by ensuring protein homeostasis. CRT and Sig-1R regulate neuronal morphogenesis and dendritic axon growth (A); Bip, SIL1, and PDI-1 regulate cortical neuron migration (C); CRT regulates Ca²⁺ to guide NGF differentiation into mature neurons (D); Bip, CNX, and Sig-1R regulate synaptic function (B). Indirect regulation mainly affects the secreted protein Reelin and AMPA and NMDA membrane receptors (C), which act on the post-synaptic membrane and nerve migration. Bip proteins are involved in endoplasmic quality control and transport misfolded proteins for degradation, thereby maintaining protein homeostasis under ER stress conditions. Insert (a) CRT cooperates with CNX and PDIA3 to form the CNX/CRT cycle that controls protein folding within the ER. The CNX/CRT cycle can specifically recognize glycoproteins linked by N2 glycosidic bonds and regulate Ca²⁺ homeostasis and Ca²⁺ signaling processes in the ER. Insert (b) Bip is involved in a variety of ER functions dependent on ATP-induced conformational changes. The adenosine triphosphatase (ATPase) cycle of Bip is regulated by its co-chaperones of two families, namely, the ER-localized DnaJ-like proteins (ERdjs) and the nucleotide exchange factors (NEFs). ERdjs enables Bip to stably associate with its target protein. The NEF SIL1 then mediates the release of the target protein from the upper Bip and further folds to form the mature protein. Modified from Fucikova et al. (2021), Ichhaporia and Hendershot (2021).