Highly dynamic neuronal compartments located far from the soma — such as axons, dendrites and synapses — depend on efficient protein turnover, requiring tight regulation of their local transcriptomes. Relatively little is known about the RNA processing events that occur in these compartments to maintain normal function. Dysregulation of local RNA processing and translation is emerging as a likely driver of synapse degeneration, a strong correlate of cognitive decline across a spectrum of neurodegenerative diseases, including dementia and motor neuron disease.
My research is focused on uncovering the full range of local regulatory mechanisms that RNAs undergo in active neuronal compartments, and how these are disrupted in neurodegeneration and healthy ageing.
SFPQ is a neuronally enriched RNA-binding protein that functions primarily in the nucleus as a splicing factor, but also localises to axons and dendrites, where it shapes local transcriptomes through mechanisms that remain poorly understood. Recent evidence points to a role for axonal SFPQ in local translation control, which we are currently investigating. SFPQ misregulation is a hallmark of ALS-FTD irrespective of genetic cause, positioning it as a potential common driver of pathogenesis. We are working to determine the extent to which its local functions in neurites are compromised in disease.
Ageing is the predominant risk factor for neurodegeneration, and the two processes are increasingly viewed as a continuum. In disease, splicing defects give rise to aberrant transcripts, including intron-retaining RNAs that accumulate in neurites, where they are thought to exert degenerative effects locally. Intriguingly, elevated intron retention is also a feature of healthy ageing — yet in that context it can have the opposite effect, promoting longevity. We are resolving how age-related RNA changes in neurite transcriptomes influence neuroprotection and neurodegeneration at the synapse, and exploring whether targeted manipulation of specific intron-retaining RNAs can promote synapse resilience and healthier brain ageing.
