Pantethine rescues a Drosophila model for pantothenate kinase–associated neurodegeneration

Abstract

Pantothenate kinase-associated neurodegeneration (PKAN), a progressive neurodegenerative disorder, is associated with impairment of pantothenate kinase function. Pantothenate kinase is the first enzyme required for de novo synthesis of CoA, an essential metabolic cofactor. The pathophysiology of PKAN is not understood, and there is no cure to halt or reverse the symptoms of this devastating disease. Recently, we and others presented a PKAN Drosophila model, and we demonstrated that impaired function of pantothenate kinase induces a neurodegenerative phenotype and a reduced lifespan. We have explored this Drosophila model further and have demonstrated that impairment of pantothenate kinase is associated with decreased levels of CoA, mitochondrial dysfunction, and increased protein oxidation. Furthermore, we searched for compounds that can rescue pertinent phenotypes of the Drosophila PKAN model and identified pantethine. Pantethine feeding restores CoA levels, improves mitochondrial function, rescues brain degeneration, enhances locomotor abilities, and increases lifespan. We show evidence for the presence of a de novo CoA biosynthesis pathway in which pantethine is used as a precursor compound. Importantly, this pathway is effective in the presence of disrupted pantothenate kinase function. Our data suggest that pantethine may serve as a starting point to develop a possible treatment for PKAN.coenzyme A | mitochondria | PKAN | oxidative stress | lifespan

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

“…Previously, it was demonstrated that CSE deficiency is linked to increased levels of oxidative stress (42). As a readout for oxidative stress, we used OxyBlot analysis as previously described (43). SCA3 flies showed increased levels of oxidized proteins (characteristically visible as multiple bands) compared with their isogenic non-SCA3 control lines (Figures 4C, D).…”

CoA protects against the deleterious effects of caloric overload in Drosophila

“…As an additional dietary approach, we tested whether adding cysteine to pantothenate could improve any HS-induced Because steady-state levels of metabolites do not refl ect the metabolic fl ux through that pathway, we took a functional approach to test whether the conversion of pantothenate to CoA was important for tolerance of HS diets. We targeted two enzymes that catalyze CoA synthesis from pantothenate, the rate-limiting pantothenate kinase ( PK also known as fumble , CG5725 ) and phosphopantothenoylcysteine synthase ( PPCS , CG5629 ), which, like fumble , is required for growth of Drosophila S2 cells ( 31 ). Because the FB is the primary site of TG synthesis in the fl y, we used FB-specifi c RNAi to reduce CoA biosynthesis from pantothenate by targeting PK/fumble and PPCS in this tissue ( Fig.…”

D-Pantethine Has Vitamin Activity Equivalent to D-Pantothenic Acids for Recovering from a Deficiency of D-Pantothenic Acid in Rats

“…In samples of rat livers, d-pantethine was shown to be more efficient than d-PaA in inducing the synthesis of CoA, but d-pantethine failed to affect the mitochondrial CoA contents if added to isolated mitochondria (8). Rana et al (9) reported that d-pantethine rescued pantothenate kinase-associated neurodegeneration in Drosophilia. These reports (6)(7)(8)(9) suggest that the efficacy of d-pantethine as a CoA precursor is dependent upon the particular organism and imply that d-pantethine may be a precursor of CoA as well as d-PaA in mammals.…”

“…Rana et al (9) reported that d-pantethine rescued pantothenate kinase-associated neurodegeneration in Drosophilia. These reports (6)(7)(8)(9) suggest that the efficacy of d-pantethine as a CoA precursor is dependent upon the particular organism and imply that d-pantethine may be a precursor of CoA as well as d-PaA in mammals. The synthetic pathway could be: d-pantethine→d-pantetheine→ 4′-phosphopantetheine→dephospho-CoA→CoA and/or d-pantethine→d-pantetheine→d-PaA→4′-phosphopantothenic acid→4′-phosphopantothenylcysteine→4′-phosphopantetheine→dephospho-CoA→CoA.…”