New research led by Prof Edward Avezov (UK DRI at Cambridge) reveals how the architecture of the cell’s transport network, the endoplasmic reticulum, can go awry and lead to problems with signalling in the brain cell in conditions like Alzheimer’s. The study, published in Advanced Science, could lead to new therapeutic approaches for neurodegenerative conditions.
What was the challenge?
The endoplasmic reticulum is a special folded network of pipes, like a tiny plumbing system, which act as a major manufacturing and transport network inside cells
The shape of this network is tightly controlled by specialised proteins, which when dysfunctional particularly affect and are linked to a range of neurodegenerative conditions from hereditary spastic paraplegia to Alzheimer’s and amyotrophic lateral sclerosis. In this study, scientists aimed to understand why brain cells are particularly vulnerable to changes in the shape of the endoplasmic reticulum.
What did the team do and what did they find?
Using neurons made in the lab from human stem cells, the team investigated how the endoplasmic reticulum handles calcium – an essential chemical needed for neurons to send electrical signals to each other (‘fire’). They found that the endoplasmic reticulum – a storage tank for calcium – is the source of calcium fuelling neuronal firing. To fire repeatedly, a cell needs to quickly top up its calcium supply after each burst. The calcium gets moved around and restocked from calcium pools outside the cell, via the pipes of the endoplasmic reticulum.
The researchers discovered that when the shape of the pipes becomes disrupted, such as in disease, calcium can no longer flow efficiently to where it’s needed. This means the cell can’t restock fast enough to keep firing.
Our study shifts the attention in dementia research from the usual focus on individual components of the cell, to the physical design and how it makes the cell functionally fragile. We discovered that it’s about the shape of the cell’s plumbing system – which when disrupted, prevents cells from recharging fast enough and stops them from firing signals. Harnessing this may present a new therapeutic approach.
Group Leader
What is the impact?
This work highlights a potential therapeutic avenue: restoring normal function in the endoplasmic reticulum, to preserve brain function in ageing and slow or prevent neurodegeneration.
Reference: V. Davi, P. Parutto, Y. Zhang, et al. “Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates and Exposes Selective Neuronal Vulnerability.” Advanced Science13, no. 36 (2026): e21101. https://doi.org/10.1002/advs.202521101
Banner image: An image of a human neuron, as seen under high resolution microscope, with pathologically perturbed ER.