Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates and Exposes Selective Neuronal Vulnerability

Journal article

The endoplasmic reticulum (ER)’s continuous morphology is tightly controlled by ER‐shaping proteins, whose genetic or expression defects drive a spectrum of neurodegenerative disorders from Hereditary Spastic Paraplegia to Alzheimer's disease. Why perturbations in ER morphology manifest specifically in neurons remains unknown. Here, by coupling visualisation of global sub‐Hz firing bursts to ER ultrastructural manipulations in human inducible Pluripotent Stem Cells (hiPSC)‐derived cortical neurons, alongside physical simulations, we establish a key ER structure‐function principle: neuronal ER architecture dictates Ca2+ replenishment speed. Altering ER structure hinders network ER luminal connectivity and Ca2+ propagation from refill points at plasma membrane contact sites, impairing the ER's capability to supply repetitive Ca2+ bursts. The ER morpho‐regulatory control of Ca2+ refill speed thus constitutes a switch on neuronal activity. Further, perturbed ER shape also abolishes Ca2+ firing and contraction in primary skeletal muscle cells. These results expose the selective vulnerability of Ca2+‐firing cells to ER structural disruptions, rationalizing ER dysfunction in neurodegeneration and unveiling a new role for the continuous ER morphology that could apply universally to Ca2+‐firing cells.

Authors: Davi, V; Parutto, P; Zhang, Y; Konno, T; Crapart, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: Advanced Science
• Pages: e21101
• Article number: e21101
• Publication date: 2026-03-31
• Acceptance date: 2026-03-13
• DOI: 10.1002/advs.202521101
• EISSN: 2198-3844
• ISSN: 2198-3844
• Language: English
• Keywords: neuronal firing; calcium oscillations; endoplasmic reticulum Ca2+ refill; neurodegenerative diseases; modelling; human iPSC‐derived neurons; endoplasmic reticulum morphology