Pharmacological Regulation of Endoplasmic Reticulum Structure and Calcium Dynamics: Importance for Neurodegenerative DiseasesS

Abstract

The endoplasmic reticulum (ER) is the largest organelle of the cell, composed of a continuous network of sheets and tubules, and is involved in pro-tein, calcium (Ca2+), and lipid homeostasis. In neurons, the ER extends throughout the cell, both somal and axo-dendritic compartments, and is highly important for neuronal functions. A third of the proteome of a cell, secreted and membrane-bound proteins, are processed within the ER lumen and most of these proteins are vital for neuronal activity. The brain itself is high in lipid con-tent, and many structural lipids are produced, in part, by the ER. Cholesterol and steroid synthesis are strictly regulated in the ER of the blood-brain barrier protected brain cells. The high Ca2+ level in the ER lumen and low cytosolic concentration is needed for Ca2+-based intracellular signaling, for synaptic signaling and Ca2+ waves, and for preparing proteins for correct folding in the presence of high Ca2+ concentrations to cope with the high concentrations of extracellular milieu. Particularly, ER Ca2+ is controlled in axodendritic areas for proper neurito-and synaptogenesis and synaptic plasticity and remodeling. In this review, we cover the physiologic functions of the neuronal ER and discuss it in context of common neurodegenerative dis-eases, focusing on pharmacological regulation of ER Ca2+. Furthermore, we postulate that heterogeneity of the ER, its protein folding capacity, and ensuring Ca2+ regulation are crucial factors for the aging and selective vulnerability of neurons in various neurodegenera-tive diseases. Significance Statement——Endoplasmic reticulum (ER) Ca2+ regulators are promising therapeutic targets for degenerative diseases for which efficacious drug therapies do not exist. The use of pharmacological probes targeting maintenance and restoration of ER Ca2+ can provide restoration of protein homeostasis (e.g., folding of complex plasma membrane signaling re-ceptors) and slow down the degeneration process of neurons.