G4C2 Hexanucleotide repeat expansions within the gene C9ORF72 are the most common cause of the neurodegenerative diseases Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD). This disease-causing expansion leads to a reduction in C9ORF72 expression levels in patients, suggesting haploinsufficiency could contribute to disease. To further understand the consequences of C9ORF72 deficiency in vivo, we generated a c9orf72 mutant zebrafish line. Analysis of the spinal cord revealed no appreciable neurodegenerative pathology such as loss of motor neurons, or increased levels of neuroinflammation. However, detailed examination of c9orf72-/- retinas showed prominent neurodegenerative features, including a decrease in retinal thickness, gliosis, and an overall reduction in neurons of all subtypes. Structurally, analysis of rod and cone cells within the photoreceptor layer showed a disturbance in the outer cells of the retina and rhodopsin mis-localisation from rod outer segments to their cell bodies and synaptic endings. Thus, C9ORF72 may play a previously unappreciated role in retinal homeostasis and suggests C9ORF72 deficiency can induce tissue specific neuronal loss.

C9ORF72 deficiency results in degeneration of the zebrafish retina in vivo