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Gene regulation mechanism impacting diverse neuropathologies uncovered


In an exciting new paper, Pat Gordon, Fursham Hamid, Eugene Makeyev and Corinne Houart have uncovered a gene regulation mechanism that has broad relevance to neuropathologies.

The paper, published in Nature Communications, focuses on the RNA-binding protein, SFPQ (Splicing Factor Proline/Glutamine Rich), a ubiquitously expressed RNA binding protein with diverse roles that has been linked to many neurological conditions including Alzheimer’s disease, amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia. The protein plays an important role in neuronal development and alternative splicing yet only a few RNA targets of SFPQ have been identified.

Gordon, Hamid et al, in an elegant series of experiments,  used an sfpq mutant zebrafish model to examine the molecular properties of the protein and understand how it affects the editing and processing of RNA. The authors found that loss of sfpq leads to the premature termination of multiple transcripts due to widespread activation of cryptic last axons (CLEs), previously unannotated. SFPQ protects neuronal genes from forming unusually short RNAs (CLE transcripts). CLE transcripts appear largely in long introns of neuronal genes and can, when activated, affect normal gene function.

Exploring their findings, Gordon, Hamid et al demonstrate how a peptide encoded by the CLE-containing epha4b mRNA isoform, which is only produced when SFPQ is absent, is responsible for neurodevelopmental defects observed in the zebrafish SFPQ-deficient model.  The  CLE-repressing activity of SFPQ uncovered in this work, is conserved between mouse and human and CLEs are found in ALS patient iPSC-derived neurons.

The compelling work is the first evidence of a gene regulation with broad relevance to neuropathologies across the lifespan and advances our understanding of SFPQ function and activity.