Abnormal Vasculature Development in Zebrafish Embryos with Reduced Expression of Pantothenate Kinase 2 Gene

Abstract

Mutations in pank2 gene encoding pantothenate kinase 2 determine a pantothenate kinaseassociated neurodegeneration, a rare disorder characterized by iron deposition in the globus pallidus. To extend our previous work, we performed microinjections of a new pank2-specific morpholino to zebrafish embryos and thoroughly analyzed vasculature development. Vessels development was severely perturbed in the head, trunk, and tail, where blood accumulation was remarkable and associated with dilation of the posterior cardinal vein. This phenotype was specific as confirmed by p53 expression analysis and injection of the same morpholino in pank2-mutant embryos. We can conclude that pank2 gene is involved in vasculature development in zebrafish embryos. The comprehension of the underlining mechanisms could be of relevance for understanding of pantothenate kinase-associated neurodegeneration.

Redesigning therapies for pantothenate kinase–associated neurodegeneration

“…Zebrafish model: Models of PKAN in Zebrafish have also identified key avenues for further study of PKAN pathogenesis (20,25). Attempts to create PKAN models in zebrafish have largely focused on generating PANK2 hypomorphic mutants in tadpoles and adult fish.…”

“…There were also several vascular defects, including edema in the heart regions and caudal plexus, as well as hemorrhaging (25). In another study, overexpression of wild-type human PANK2 and mutant zebrafish PANK2 mRNA was achieved in zebrafish embryos (25) and was found to cause vascular and neurological defects and reduced locomotor behavior (25). While neurological defects are predictable in a model of PKAN, vascular J o u r n a l P r e -p r o o f defects have not been described in any other model of PKAN.…”

“…In recent years, several animal models of PKAN have been developed, but translation of this knowledge to humans is hampered by physiological and metabolic differences between model organisms and humans ( 11 , 13 , 14 , 15 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ). One key difference is that while all the species used share a homologous pantothenate kinase gene, the number of different orthologs and subcellular localization of the encoded proteins often vary.…”

“…In one study, knockdown was achieved via injection of a splice-inhibiting morpholino, which resulted in disturbed brain morphology and hydrocephalus ( 20 ). There were also several vascular defects, including edema in the heart regions and caudal plexus, as well as hemorrhaging ( 25 ). In another study, overexpression of mutant human PANK2 and mutant zebrafish PANK2 mRNA was achieved in zebrafish embryos ( 25 ) and found to cause vascular and neurological defects and reduced locomotor behavior ( 25 ).…”

“…However, they might also indicate a previously unexplored link between PANK2 activity and CoA homeostasis in vascular development. Importantly, overexpression of PANK2 mutant forms appears to be associated with perturbation in CoA availability, irrespective of their catalytic activity ( 25 ). This mirrors the phenomenon seen in humans where some patients have WT levels of activity in the PANK2 enzyme but still develop symptoms associated with PKAN ( 41 ).…”