Marc-David RUEPP

Senior Lecturer in Neuroscience, UK Dementia Research Institute at King’s College London, UK

Monday 2 December 2019 | 12:00 noon – ICGEB Trieste, ITALY

Direct FUS – snRNA interactions provide a molecular link between ALS and SMA

Host: E. Buratti

The RNA-binding protein Fused in Sarcoma (FUS) is a ubiquitously expressed member of the hnRNP family and has been implicated in multiple steps of gene expression. Mutations in the FUS gene have been linked to the motor neuron disease Amyotrophic Lateral Sclerosis (ALS) and typically disrupt the nuclear localization signal of FUS, leading to cytoplasmic mislocalization and eventually aggregation. To identify its binding sites in the physiological as well as pathological context, we performed an RNA- binding domain centric CLIP approach with nuclear and cytoplasmic FUS constructs.
We consistently found the spliceosomal U1 snRNA among the most enriched transcripts in our CLIP data with a well-defined binding signature on stem loop 3. Our biochemical, structural and functional data suggests that FUS might employ its two RNA-binding domains to physically bridge the U1 snRNP to its pre-mRNA substrate during splice site definition. In the disease context, we observed that cytoplasmic FUS cross-links to an additional site on the U1 snRNA overlapping with the Sm site. We show that this aberrant cytoplasmic interaction interferes with U1 snRNP biogenesis and present evidence for a general snRNP assembly defect. Intriguingly, snRNP biogenesis defects were already reported for Spinal Muscular Atrophy (SMA) implicating a direct molecular link between FUS-linked ALS and SMA.