Subcellular Neurobiology (Dafinca Group)

Protein mislocalization and aggregation are central drivers of neurodegenerative disease, disrupting essential cellular processes and leading to synaptic failure. The aim of our group’s research is to understand how intracellular protein mislocalisation and organellar crosstalk drive neuronal dysfunction in Frontotemporal dementia (FTD) and Amyotrophic lateral sclerosis (ALS).

To achieve this, we are integrating human induced pluripotent stem cell (iPSC) modelling with subcellular proteomics, super-resolution imaging, optogenetics and machine-learning tools to map protein rewiring in disease.

Our main interests are the following:

1. Understanding how mitochondrial dysfunction leads to synaptic failure in ALS/FTD. Presynaptic mitochondria are involved in many cellular processes that are relevant for neuronal function and support synaptic transmission, which breaks down in ALS/FTD. In work funded by the Motor Neurone Disease Association, we are investigating the mechanistic links between mitochondrial activity and synaptic transmission in iPSC-derived motor neurons from ALS patients.
2. Identifying local presynaptic molecular dysfunction in ALS iPS-derived neurons. In work funded by My Name’5 Doddie Foundation, we are integrating multi-omics with imaging to explore early presynaptic changes in ALS-derived motor neurons.
3. Mapping intracellular crosstalk in FTD. We use cortical neurons differentiated from patients with genetic forms of Frontotemporal dementia (FTD) to define how protein aggregation rewires the proteome and leads to functional deficits.
4. Developing complex models of disease. We are establishing complex models of neuronal communication with muscle cells and astrocytes to gain a better understanding of how these interactions modulate subcellular neuronal organisation in FTD and ALS.

The overarching goal of our research is to identify therapeutic entry points for restoring synaptic integrity and neuronal function in neurodegenerative disorders.

We always welcome enquiries for opportunities to join our group and discussions for new collaborations. If you are interested, please reach out by e-mail to Ruxandra.dafinca@ndcn.ox.ac.uk.