Neurodegeneration with brain iron accumulation (NBIA) disorders are a set of clinically analogous neurological diseases characterized by neuropathology of the basal gaglia with iron deposition (Levi and Finazzi, 2015). Patients display pyramidal and extrapyramidal movement disruption as well as cognitive decline. Mutations in 12 genes have been shown to cause NBIA and each protein has a seemingly disparate cellular function. Mutations in Pantothenate kinase 2 and Coenzyme A synthase (COASY), two genes involved in CoA biosynthesis, are among these 12 genes. While mutations in PANK2 account for 35-50% of all NBIA cases, those in COASY are extremely rare, and only 3 independent cases have been identified until now. Even though several animal models have been generated to facilitate investigation of these disease mechanisms, the molecular processes by which defects in CoA biogenesis lead to neurodegeneration is not fully understood yet. To shed new light onto the molecular link connecting COASY defects to neural mulfuntioning we investigated the role of the coasy. gene in zebrafish development. The gene has high level of sequence identity with the human ortholog and is ubiquitously expressed from the earliest stages of development. The abrogation of its expression led to strong reduction of CoA content, high lethality and a phenotype resembling to that of dorsalized mutants. Lower doses of morpholino resulted in a milder phenotype, with evident perturbation in neurogenesis and formation of vascular arborization; the dorso-ventral patterning was severely affected, the expression of bone morphogenetic protein (Bmp) receptors and activity were decreased, while cell death increased. These features specifically correlated with the block in CoA biosynthesis and were rescued by the addition of CoA to fish water and the overexpression of the human wild-type, but not mutant gene. These results confirm the absolute requirement for adequate levels of CoA for proper neural and vascular development in zebrafish and point to the Bmp pathway as a possible molecular connection underlining the observed phenotype.

Down regulation of Coasy, the gene associated with NBIA-VI, reduces Bmp signalling, perturbs dorso-ventral patterning and alters neuronal development in zebrafish

ZIZIOLI, DANIELA;TISO, NATASCIA;FACCHINELLO, NICOLA;
2017

Abstract

Neurodegeneration with brain iron accumulation (NBIA) disorders are a set of clinically analogous neurological diseases characterized by neuropathology of the basal gaglia with iron deposition (Levi and Finazzi, 2015). Patients display pyramidal and extrapyramidal movement disruption as well as cognitive decline. Mutations in 12 genes have been shown to cause NBIA and each protein has a seemingly disparate cellular function. Mutations in Pantothenate kinase 2 and Coenzyme A synthase (COASY), two genes involved in CoA biosynthesis, are among these 12 genes. While mutations in PANK2 account for 35-50% of all NBIA cases, those in COASY are extremely rare, and only 3 independent cases have been identified until now. Even though several animal models have been generated to facilitate investigation of these disease mechanisms, the molecular processes by which defects in CoA biogenesis lead to neurodegeneration is not fully understood yet. To shed new light onto the molecular link connecting COASY defects to neural mulfuntioning we investigated the role of the coasy. gene in zebrafish development. The gene has high level of sequence identity with the human ortholog and is ubiquitously expressed from the earliest stages of development. The abrogation of its expression led to strong reduction of CoA content, high lethality and a phenotype resembling to that of dorsalized mutants. Lower doses of morpholino resulted in a milder phenotype, with evident perturbation in neurogenesis and formation of vascular arborization; the dorso-ventral patterning was severely affected, the expression of bone morphogenetic protein (Bmp) receptors and activity were decreased, while cell death increased. These features specifically correlated with the block in CoA biosynthesis and were rescued by the addition of CoA to fish water and the overexpression of the human wild-type, but not mutant gene. These results confirm the absolute requirement for adequate levels of CoA for proper neural and vascular development in zebrafish and point to the Bmp pathway as a possible molecular connection underlining the observed phenotype.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11577/3228322
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