title: Induction of Neuron-Specific Degradation of Coenzyme A Models Pantothenate Kinase-Associated Neurodegeneration by Reducing Motor Coordination in Mice.
abstract: BACKGROUND
  Pantothenate kinase-associated neurodegeneration, PKAN, is an inherited disorder characterized by progressive impairment in motor coordination and caused by mutations in PANK2, a human gene that encodes one of four pantothenate kinase (PanK) isoforms. PanK initiates the synthesis of coenzyme A (CoA), an essential cofactor that plays a key role in energy metabolism and lipid synthesis. Most of the mutations in PANK2 reduce or abolish the activity of the enzyme. This evidence has led to the hypothesis that lower CoA might be the underlying cause of the neurodegeneration in PKAN patients; however, no mouse model of the disease is currently available to investigate the connection between neuronal CoA levels and neurodegeneration. Indeed, genetic and/or dietary manipulations aimed at reducing whole-body CoA synthesis have not produced a desirable PKAN model, and this has greatly hindered the discovery of a treatment for the disease.
  Cellular CoA levels are tightly regulated by a balance between synthesis and degradation. CoA degradation is catalyzed by two peroxisomal nudix hydrolases, Nudt7 and Nudt19. In this study we sought to reduce neuronal CoA in mice through the alternative approach of increasing Nudt7-mediated CoA degradation. This was achieved by combining the use of an adeno-associated virus-based expression system with the synapsin (Syn) promoter. We show that mice with neuronal overexpression of a cytosolic version of Nudt7 (scAAV9-Syn-Nudt7cyt) exhibit a significant decrease in brain CoA levels in conjunction with a reduction in motor coordination. These results strongly support the existence of a link between CoA levels and neuronal function and show that scAAV9-Syn-Nudt7cyt mice can be used to model PKAN.
authors.affiliation: Department of Biochemistry, School of Medicine, West Virginia University, Morgantown, West Virginia, United States of America.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Shumar
authors.affiliation: Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fagone
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Alfonso-Pecchio
authors.affiliation: Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: John T
authors.initials: JT
authors.lastname: Gray
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Jerold E
authors.initials: JE
authors.lastname: Rehg
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jackowski
authors.affiliation: Department of Biochemistry, School of Medicine, West Virginia University, Morgantown, West Virginia, United States of America.
authors.forename: Roberta
authors.initials: R
authors.lastname: Leonardi
mesh_terms: D000818:Animals; D003065:Coenzyme A / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D009474:Neurons / Q000378:metabolism*; D006211:Pantothenate Kinase-Associated Neurodegeneration / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011755:Pyrophosphatases / Q000235:genetics* / Q000378:metabolism; D000096964:Nudix Hydrolases
chemical_list: D003065:Coenzyme A; D011755:Pyrophosphatases; D000096964:Nudix Hydrolases