title: Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model.
abstract: Pantothenate kinase-associated neurodegeneration, caused by mutations in the PANK2 gene, is an autosomal recessive disorder characterized by dystonia, dysarthria, rigidity, pigmentary retinal degeneration and brain iron accumulation. PANK2 encodes the mitochondrial enzyme pantothenate kinase type 2, responsible for the phosphorylation of pantothenate or vitamin B5 in the biosynthesis of co-enzyme A. A Pank2 knockout (Pank2(-/-)) mouse model did not recapitulate the human disease but showed azoospermia and mitochondrial dysfunctions. We challenged this mouse model with a low glucose and high lipid content diet (ketogenic diet) to stimulate lipid use by mitochondrial beta-oxidation. In the presence of a shortage of co-enzyme A, this diet could evoke a general impairment of bioenergetic metabolism. Only Pank2(-/-) mice fed with a ketogenic diet developed a pantothenate kinase-associated neurodegeneration-like syndrome characterized by severe motor dysfunction, neurodegeneration and severely altered mitochondria in the central and peripheral nervous systems. These mice also showed structural alteration of muscle morphology, which was comparable with that observed in a patient with pantothenate kinase-associated neurodegeneration. We here demonstrate that pantethine administration can prevent the onset of the neuromuscular phenotype in mice suggesting the possibility of experimental treatment in patients with pantothenate kinase-associated neurodegeneration.
authors: 1 Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy.
authors: Dario
authors: D
authors: Brunetti
authors: Sabrina
authors: S
authors: Dusi
authors: Carla
authors: C
authors: Giordano
authors: Costanza
authors: C
authors: Lamperti
authors: Michela
authors: M
authors: Morbin
authors: Valeria
authors: V
authors: Fugnanesi
authors: Silvia
authors: S
authors: Marchet
authors: Gigliola
authors: G
authors: Fagiolari
authors: Ody
authors: O
authors: Sibon
authors: Maurizio
authors: M
authors: Moggio
authors: Giulia
authors: G
authors: d'Amati
authors: Valeria
authors: V
authors: Tiranti
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D055423:Diet, Ketogenic / Q000009:adverse effects*; D004734:Energy Metabolism / Q000502:physiology; D005260:Female; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D007150:Immunohistochemistry; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008928:Mitochondria / Q000473:pathology; D009048:Motor Skills / Q000502:physiology; D009474:Neurons / Q000473:pathology; D010204:Pantetheine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017933:Peripheral Nervous System / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000502:physiology; D012584:Sciatic Nerve / Q000473:pathology; D014280:Triglycerides / Q000097:blood
chemical_list: D014280:Triglycerides; D010204:Pantetheine; C005425:pantethine; D002784:Cholesterol; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase
keywords: ketogenic diet; mitochondria; pantethine; pantothenate kinase-associated neurodegeneration (PKAN)