As an organelle responsible for the production, processing and transport of a wide variety of cellular materials, the endoplasmic reticulum (ER) plays a central role in maintaining protein quality in the cell. Pathological conditions that affect protein folding or calcium signaling can interfere with this role, causing stress to the ER which, in severe cases, can trigger cell death (apoptosis). In the brain, such apoptosis has been associated with neurodegenerative diseases such as Alzheimer's disease and Huntington's disease (HD), yet the mechanisms involved remain poorly understood.
To clarify these mechanisms, the researchers investigated the relationship between ER stress and a neuronal protein called inositol 1,4,5-trisphosphate receptor 1 (IP3R1), one of three IP3R receptors that modulate intracellular calcium signaling. Using calcium imaging techniques, the team identified a sharp decline in IP3R1 activity in cells treated with ER stress inducers. It was further revealed that the ER stress-dependent dysfunction of IP3R1 induced neuronal cell death and brain damage, situating IP3R1 as a crucial link between ER stress and neuron cell death.
Underlying this link, the researchers identified a mechanism through which GRP78, a molecular chaperone, binds to a region of IP3R1 called L3V to positively regulate tetrameric assembly of IP3R1. ER stress, they show, impairs this assembly mechanism and subsequently inhibits IP3R1 activation, a process also observed in the brain of model mice with HD.
As the first research to highlight the significant role of IP3R1 in protecting the brain from ER stress, the Neuron study marks a major step toward clarifying the mechanisms underlying stress-induced brain damage, promising advancements in the treatment of neurodegenerative diseases.