Theme: Mechanisms

Project Description

Bipolar disorder and schizophrenia urgently need treatments grounded in mechanism. Genetic studies consistently implicate neuronal calcium signalling, but common risk variants have small effects and are hard to turn into drug targets. This PhD starts instead from a rare disorder with a strong psychiatric signal.

Darier disease, a skin condition caused by loss-of-function variants in ATP2A2, carries a 4.3-fold increased risk of bipolar disorder and a 2.3-fold increased risk of schizophrenia as well as increased rates of epilepsy. ATP2A2 encodes SERCA2, the pump that refills the endoplasmic reticulum’s calcium stores after neuronal activity. The same gene emerges independently from the largest schizophrenia genomic (GWAS) studies, and mice with reduced brain Atp2a2 show slowed calcium clearance and a hyperdopaminergic state. One gene and one druggable mechanism therefore link rare and common risk.

Two critical gaps remain, which will be addressed in this PhD:

• Isoforms: We don’t know which SERCA2 isoforms the human brain expresses, or whether their balance is altered in psychiatric illness. You will use targeted long-read sequencing of post-mortem prefrontal cortex to find out.
• Human neuronal models: No human neuronal model of ATP2A2 deficiency exists. You will build one from CRISPR-edited and patient-derived iPSC cortical neurons, measuring calcium dynamics by imaging and network activity by multi-electrode arrays.

We will then use this information to screen repurposing candidates, including SERCA activators, dantrolene and anti-epileptic drugs, to test whether these neuronal phenotypes can be reversed.

What you will gain: hands-on training in long-read transcriptomics, stem-cell neuronal models, functional neurophysiology and drug screening. The project will deliver a human cellular platform for calcium-targeted drug discovery and nominate candidates for experimental medicine studies.

This is an ideal fit for clinicians who want to understand mental illness at its biological roots and develop pathways to new treatments.