Associated organisationsUniversitat Ulm · University College London · University of OxfordEurope PMC affiliations are not treated as award recipients or mapped locations.
Funding£3.7M
PeriodMay 2022 — Apr 2027
In plain English
AI plain-English summary
In Parkinson’s disease, a small set of brain cells called dopamine neurons die off, while their near-identical neighbours survive unscathed. This project aims to find out why. The researchers suspect the answer lies in how these vulnerable neurons handle calcium—a chemical signal that surges every time the cell fires. They will track calcium movement through the entire length of living dopamine neurons, from the cell body to the far-off nerve endings, during normal activity patterns. Using both mouse models and human stem-cell-derived neurons, they will compare resistant and susceptible cells to see where calcium enters, how organelles cope with the load, and whether this process breaks down under the stress of Parkinson’s disease. This is fundamental science. It will not produce a new drug or diagnostic test. But it addresses a central puzzle: why Parkinson’s destroys only specific neurons. Understanding that selectivity—moving from correlation to causation—could eventually guide therapies that protect the vulnerable cells, or reveal why existing treatments fail. Similar mechanistic work on neuronal vulnerability has, in the past, opened unexpected routes to slowing neurodegeneration.
View original technical description
The development of improved therapies for Parkinson’s disease (PD) requires new knowledge of why certain types of neuron dysfunction and die. Midbrain dopaminergic neurons (DANs) are particularly impacted by PD, and offer valuable opportunities for comparative investigations of factors underpinning vulnerability. Our interdisciplinary collaboration will address the overarching hypothesis that compartmentalised, activity-dependent Ca2+ handling in DANs is cell-type-specific, perturbed by disease burden, and contributes to preferential vulnerability in Parkinson's. We will collectively deliver a step change in the understanding of calcium dynamics and related dopaminergic signalling in DANs. We will be the first to define cytosolic and organellar calcium dynamics throughout the whole extent of DANs during physiologically-relevant activity patterns. Our programme brings together leading scientists with complementary expertise, and integrated experimental platforms spanning mouse models and human stem cell-derived models, to identify the key mechanisms involved. Progressing from correlation to causation in the contexts of health and PD, we will define how and when calcium enters susceptible and resistant DANs, its handling by organelles in light of their other functions, and the importance of compartmentalised calcium for how DANs cope with PD burden. Our collaborative approach is strongly positioned to transform understanding of selective neuronal vulnerability in PD.
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