Signaling pathways to degeneration and resilience

About the project

Our laboratory is focussed in the molecular mechanisms of core interdependent pathological processes upon which several neurological disorders, including ALS, converge, including oxidative stress, mitochondrial dysfunction, inflammation, and abberant Ca2+ handling. Additionally, we are interested in the brain's capacity for homeostasis, particularly the ability of neurons and astrocytes to mount adaptive protective responses to adverse conditions.

For example, we contribute to knowledge of the molecular mechanisms underlying both the neuroprotective and neurodestructive effects of Ca2+ signals, as well as the factors that determine whether signals are harmful or beneficial. The coordinated transcriptional changes that underlie Ca2+-dependent neuroprotective effects are also a focus, including new investigations into Ca2+-dependent transcriptional control in human stem cell-derived neurons. In addition, we research into molecular mechanisms of Ca2+-mediated excitotoxicity involving NMDA receptor channel subunit composition and mitochondrial dysfunction. Another core interest is the key neuroprotective role played by astrocytes  and how neurons may communicate their needs to them. More recently, we have been investigating  with collaborators the impact of disease pathology on astrocytic function and how this in turn impacts on neuronal properties.


Medical Research Council, Alzheimer’s Research UK, Alzheimer’s Society


Jiwaji Z, Tiwari SS, Avilés-Reyes RX, Hooley M, Hampton D, Torvell M, Johnson DA, McQueen J, Paul Baxter P, Sabari-Sankar K, Qiu J, He X, Fowler J, Febery J, Gregory J, Rose J, Tulloch J, Story D, McDade K, Smith AM, Greer P
Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology
Nature Communications 2022. Jan 10;13(1):135.
Patani, R., Hardingham, G. E. & Liddelow, S. A
Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration
Nature Reviews Neurology 2023. 19: 395-409.
Hardingham GE, Pruunsild P, Greenberg ME, Bading H
Lineage divergence of activity-driven transcription and evolution of cognitive ability
Nat Rev Neurosci. 2018 Jan;19(1):9-15
Hardingham GE, Do KQ
Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis
Nat Rev Neurosci. 2016 Feb;17(2):125-34

Primary location


Principal Investigator

Other people involved

The group: Kirsty Haddow, Zoeb Jiwaji, Mosi Li, Jamie Loan, Laoise Casserly, Kyle Wardlaw, Katherine Ridley, Alison Harris, Deepali Vasoya, Owen Dando, Juraj Koudelka, Xin He, Lynsey Dunsmore, Alexa Jury, Beverly Roberts

University of Edinburgh: Siddharthan Chandran, Jill Fowler, Seth Grant, Karen Horsburgh, Peter Kind, Noboru Komiyama, Barry McColl, Tara Spires-Jones, David Wyllie, Joanna Wardlaw, Anna Williams, Blanca Diaz-Castro, Jian Gan, David Hunt, Josef Priller, Axel Montagne, Patricio Opazo, Veronique Miron, Kat Bowles, Philip Hasel.