title: Mitochondrial dysfunction in NnaD mutant flies and Purkinje cell degeneration mice reveals a role for Nna proteins in neuronal bioenergetics.
abstract: The Purkinje cell degeneration (pcd) mouse is a recessive model of neurodegeneration, involving cerebellum and retina. Purkinje cell death in pcd is dramatic, as >99% of Purkinje neurons are lost in 3 weeks. Loss of function of Nna1 causes pcd, and Nna1 is a highly conserved zinc carboxypeptidase. To determine the basis of pcd, we implemented a two-pronged approach, combining characterization of loss-of-function phenotypes of the Drosophila Nna1 ortholog (NnaD) with proteomics analysis of pcd mice. Reduced NnaD function yielded larval lethality, with survivors displaying phenotypes that mirror disease in pcd. Quantitative proteomics revealed expression alterations for glycolytic and oxidative phosphorylation enzymes. Nna proteins localize to mitochondria, loss of NnaD/Nna1 produces mitochondrial abnormalities, and pcd mice display altered proteolytic processing of Nna1 interacting proteins. Our studies indicate that Nna1 loss of function results in altered bioenergetics and mitochondrial dysfunction.
authors.affiliation: School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG72UH, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Chakrabarti
authors.forename: Rabaab
authors.initials: R
authors.lastname: Zahra
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Jackson
authors.forename: Parsa
authors.initials: P
authors.lastname: Kazemi-Esfarjani
authors.forename: Bryce L
authors.initials: BL
authors.lastname: Sopher
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Mason
authors.forename: Thomas
authors.initials: T
authors.lastname: Toneff
authors.forename: Soyoung
authors.initials: S
authors.lastname: Ryu
authors.forename: Scott
authors.initials: S
authors.lastname: Shaffer
authors.forename: Janice W
authors.initials: JW
authors.lastname: Kansy
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Eng
authors.forename: Gennifer
authors.initials: G
authors.lastname: Merrihew
authors.forename: Michael J
authors.initials: MJ
authors.lastname: MacCoss
authors.forename: Anne
authors.initials: A
authors.lastname: Murphy
authors.forename: David R
authors.initials: DR
authors.lastname: Goodlett
authors.forename: Vivian
authors.initials: V
authors.lastname: Hook
authors.forename: Craig L
authors.initials: CL
authors.lastname: Bennett
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Pallanck
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002461:Cell Line, Transformed; D002531:Cerebellum / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008928:Mitochondria / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000473:pathology*; D010641:Phenotype; D040901:Proteomics / Q000379:methods; D011689:Purkinje Cells / Q000378:metabolism* / Q000648:ultrastructure; D012160:Retina / Q000473:pathology / Q000648:ultrastructure; D012162:Retinal Degeneration / Q000235:genetics / Q000503:physiopathology; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic / Q000379:methods; D014162:Transfection / Q000379:methods
chemical_list: D029721:Drosophila Proteins; D049452:Green Fluorescent Proteins; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase; C420042:Agtpbp1 protein, mouse; D019204:GTP-Binding Proteins