Homozygous CADPS2 mutations cause neurodegenerative disease with Lewy bodies in parrots

Background: Several genetic models that recapitulate neurodegenerative features of Parkinson's disease (PD) exist, which have been largely based on genes discovered in monogenic PD families. However, spontaneous genetic mutations have not been linked to the pathological hallmarks of PD in non-human vertebrates. Objective: To describe the genetic and pathological findings of three yellow crowned parrot (Amazona ochrocepahala) siblings with a severe and rapidly progressive neurological phenotype. Methods: The phenotype of the three parrots included severe ataxia, head tilt, and stargazing, while their parents were phenotypically normal. Tests to identify avian viral infections and brain imaging studies were all negative. Due to their inability to survive independently, they were all euthanized at age 3 months and their brains underwent neuropathological examination and proteosome activity assays. Whole genome sequencing (WGS) was performed on the three affected parrots and their parents. Results: The brains of affected parrots exhibited neuronal loss, spongiosis, and Lewy bodies in the neocortex, amygdala, hypothalamus, periaqueductal gray matter, dorsal vagal nucleus, in some cerebellar Purkinje cells, and in the basal ganglia. Proteasome activity was significantly reduced in the affected parrots compared to a control (p<0.05). WGS identified a single homozygous missense mutation (p.V559L) in a highly conserved amino acid residue within the pleckstrin homology (PH) domain of the Calcium Dependent Secretion Activator 2 (CADPS2) gene. Mutations in the CADPS2 PH domain may affect α-synuclein aggregation, since this is the domain that binds α-synuclein selectively to interact with other proteins. Interestingly, CADPS2 expression is regulated by two well-known PD genes, LRRK2 and SNCA. Conclusions: Our data suggest that a homozygous mutation in the CADPS2 gene causes a severe neurodegenerative phenotype with Lewy bodies in parrots. Although CADPS2 variants have not been reported to cause PD in humans, further investigation of the gene in model organisms might provide important insights into the pathophysiology of Lewy body disorders. ### Competing Interest Statement The authors have declared no competing interest.