Embryonic spinocerebellar ataxia type 37-associated AUUUC repeat RNA causes neurodevelopmental defects

Onset of many neurodegenerative and neuromuscular diseases usually starts in adulthood; however, recent advances point towards neurodevelopmental changes as drivers of late neurodegeneration. How early neuropathological features occur under these conditions remains unclear, but this knowledge would be critical for timely therapeutic intervention. Here, we provide evidence that neurodevelopmental axonal defects initiate a motor phenotype in a zebrafish model of spinocerebellar ataxia type 37 (SCA37), a degenerative hereditary disease caused by an ATTTC repeat in the DAB1 gene. We investigated neuronal defects triggered by the embryonic AUUUC repeat RNA from the DAB1 gene and their effects later in life by transiently expressing this RNA in embryos and analyzing innervation and motor function. We found abnormalities in motor neuron axonal outgrowth and muscle innervation. We also discovered disrupted embryonic motor activity, and reduced locomotor distance and velocity in late adult zebrafish, demonstrating motor impairment. Moreover, we showed that protein expression of the splicing regulator NOVA2 rescues axonal defects, indicating dysfunction of NOVA2-regulated neurodevelopmental processes. Overall, our results establish embryonic expression of the AUUUC repeat RNA as a driver of axonal and synaptic abnormalities, interfering with neuronal circuits and culminating in adult motor dysfunction.