Coenzyme A (CoA) is a key molecule involved in several metabolic processes such as tricarboxylic acid cycle, fatty acid metabolism, amino acid biosynthesis, and histone and non-histone protein acetylation. Defects in CoA biosynthetic enzymes are associated with PKAN and CoPAN disorders characterized by progressive neurodegeneration and iron deposition in the brain. PKAN is caused by mutations in PANK2, encoding the pantothenate kinase 2 (Pank2), the first step of the CoA biosynthesis, whereas mutations in CoA synthase (CoASY), involved in the catalysis of the last two steps of the CoA biosynthetic pathway, have been reported as the second inborn error of CoA synthesis. Although iron accumulation is a hallmark of these forms of neurodegeneration, its relationship with CoA dysfunction is not yet clear and many questions concerning their pathogenesis remain unanswered, in particular whether or not iron accumulation is the primary cause of the disease. Different models of these disorders have been developed representing important tools for the study of the molecular events linking deficiency of CoA biosynthesis to neurodegenerative process. We constructed and characterized yeast model for PKAN and CoPAN, namely S. cerevisiae strains expressing a pathological variant of COASY or of CAB1, the unique yeast gene encoding Pank. This mutant strains recapitulate the disease phenotypes: mitochondrial dysfunction, altered lipid metabolism, iron overload and oxidative damage thus representing a useful model to clarify the pathogenesis underlying these diseases. Taking advantage of the respiratory deficient phenotype of the PKAN yeast model we performed a screening of a collection of 1018 FDA-approved drugs (Selleck Library) in order to identify chemical suppressors i.e. potential therapeutic drugs for PKAN treatment. Two molecules in particular were found, CRM1 and CRM2 able to revert the respiratory defect. Moreover preliminary results indicated that both compounds could revert the other phenotypes associated to CoA deficiency; in particular, iron, ROS content, and lipid peroxidation.

A yeast model for PKAN and CoPAN neurodegeration / CECCATELLI BERTI, Camilla; Goffrini, Paola. - (2018).

A yeast model for PKAN and CoPAN neurodegeration

Camilla Ceccatelli Berti;Paola Goffrini
2018

Abstract

Coenzyme A (CoA) is a key molecule involved in several metabolic processes such as tricarboxylic acid cycle, fatty acid metabolism, amino acid biosynthesis, and histone and non-histone protein acetylation. Defects in CoA biosynthetic enzymes are associated with PKAN and CoPAN disorders characterized by progressive neurodegeneration and iron deposition in the brain. PKAN is caused by mutations in PANK2, encoding the pantothenate kinase 2 (Pank2), the first step of the CoA biosynthesis, whereas mutations in CoA synthase (CoASY), involved in the catalysis of the last two steps of the CoA biosynthetic pathway, have been reported as the second inborn error of CoA synthesis. Although iron accumulation is a hallmark of these forms of neurodegeneration, its relationship with CoA dysfunction is not yet clear and many questions concerning their pathogenesis remain unanswered, in particular whether or not iron accumulation is the primary cause of the disease. Different models of these disorders have been developed representing important tools for the study of the molecular events linking deficiency of CoA biosynthesis to neurodegenerative process. We constructed and characterized yeast model for PKAN and CoPAN, namely S. cerevisiae strains expressing a pathological variant of COASY or of CAB1, the unique yeast gene encoding Pank. This mutant strains recapitulate the disease phenotypes: mitochondrial dysfunction, altered lipid metabolism, iron overload and oxidative damage thus representing a useful model to clarify the pathogenesis underlying these diseases. Taking advantage of the respiratory deficient phenotype of the PKAN yeast model we performed a screening of a collection of 1018 FDA-approved drugs (Selleck Library) in order to identify chemical suppressors i.e. potential therapeutic drugs for PKAN treatment. Two molecules in particular were found, CRM1 and CRM2 able to revert the respiratory defect. Moreover preliminary results indicated that both compounds could revert the other phenotypes associated to CoA deficiency; in particular, iron, ROS content, and lipid peroxidation.
A yeast model for PKAN and CoPAN neurodegeration / CECCATELLI BERTI, Camilla; Goffrini, Paola. - (2018).
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2861663
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