I joined the Centre at King’s in September 2015. During my MRes year, I carried out rotations in the labs of Professor Jon Clarke, Professor Corinne Houart and Dr. Setsuko Sahara. In summer 2016, I decided to return to Corinne’s lab in order to undertake my PhD, which is involved in analysing the non-nuclear roles of splicing factors, such as SFPQ, in motor neuron development and neurodegeneration.
Cell structure and function are largely defined by the complement of proteins being expressed. Neurons are especially complex cells, expressing around 10,000 different protein types at any one time. They also have sophisticated morphologies, with functionally different cell compartments residing huge distances apart and from the nucleus. One remote region, the synapse, is highly metabolically active, experiencing rapid protein turnover during development. This presents a unique challenge for neurons: ensuring efficient protein dynamics far from the nucleus. Recent research has shed light onto the wealth of RNA processing events that take place following gene transcription to facilitate neuronal differentiation and homeostasis. A better understanding of RNA processing has huge potential benefits in tackling neurodegenerative disease.
SFPQ is a multifunctional RNA-binding protein expressed ubiquitously in nuclei, implicated primarily in pre-mRNA splicing. Recently, extranuclear expression of SFPQ, intron-retaining transcripts and other spliceosomal proteins has been observed in motor neuron axons. The extranuclear roles of SFPQ remain enigmatic, despite a relatively good understanding of its nuclear functions. SFPQ null zebrafish embryos display a striking phenotype including no motility accompanied by failed motor axon extension, rescued upon expression of an exclusively cytoplasmic SFPQ variant. In mammalian sensory neurons extranuclear SFPQ is required for axonal localisation of mRNAs essential for axonal survival. These findings strongly suggest that extranuclear SFPQ is vital for healthy motor axon extension and maintenance, but further research is necessary in order to explore exactly how and why. Interestingly, point mutations in the gene encoding SFPQ have been identified in patients suffering from ALS, a disease characterised primarily by motor neuron degeneration.