Endoplasmic Reticulum Malfunction in the Nervous System

Abstract

Neurodegenerative diseases often have multifactorial causes and are progressive diseases. Some are inherited while others are acquired, and both vary greatly in onset and severity. Impaired endoplasmic reticulum (ER) proteostasis, involving Ca²⁺ signaling, protein synthesis, processing, trafficking, and degradation, is now recognized as a key risk factor in the pathogenesis of neurological disorders. Lipidostasis involves lipid synthesis, quality control, membrane assembly as well as sequestration of excess lipids or degradation of damaged lipids. Proteostasis and lipidostasis are maintained by interconnected pathways within the cellular reticular network, which includes the ER and Ca²⁺ signaling. Importantly, lipidostasis is important in the maintenance of membranes and luminal environment that enable optimal protein processing. Accumulating evidence suggest that the loss of coordinate regulation of proteostasis and lipidostasis has a direct and negative impact on the health of the nervous system.

Keywords: calnexin; endoplasmic reticulum; lipidostasis; neurological disorders; proteostasis.

Figure 1

Cell stress coping responses and the interplay between proteostasis and lipidostasis. Proteostasis refers to optimal protein biosynthesis and trafficking whereas lipidostasis pertains to optimal lipid biosynthesis, trafficking, and membrane assembly. Both of these processes rely on the availability of energy (ATP), and nutrients (such as Ca²⁺, sugars, amino acids, lipid subunits, nucleotides, other essential cofactors). When cells experience external or internal insults that result in the loss of control of nutrient and energy metabolism corrective strategies (UPR, GDR, autophagy, other coping responses) are activated to counteract and eliminate cell stress. The regulatory and metabolic pathways that operate to recover proteostasis and lipidostasis are interconnected, and support each other in preserving global cellular homeostasis.