Mitochondrial Dysfunction in NnaD Mutant Flies and Purkinje Cell Degeneration Mice Reveals a Role for Nna Proteins in Neuronal Bioenergetics

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 carboxypeptidas...

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Published in:Neuron (Cambridge, Mass.) Mass.), 2010-06, Vol.66 (6), p.835-847
Main Authors: Chakrabarti, Lisa, Zahra, Rabaab, Jackson, Stephen M., Kazemi-Esfarjani, Parsa, Sopher, Bryce L., Mason, Amanda G., Toneff, Thomas, Ryu, Soyoung, Shaffer, Scott, Kansy, Janice W., Eng, Jeremiah, Merrihew, Gennifer, MacCoss, Michael J., Murphy, Anne, Goodlett, David R., Hook, Vivian, Bennett, Craig L., Pallanck, Leo J., La Spada, Albert R.
Format: Article
Language:English
Subjects:
Age
Animals
Animals, Genetically Modified
Ataxia
Binding sites
Cell division
Cell Line, Transformed
CELLBIO
Cerebellum - pathology
Cerebellum - ultrastructure
Dehydrogenases
Disease Models, Animal
Drosophila
Drosophila Proteins - genetics
Energy Metabolism - genetics
Enzymes
Gene Expression Regulation - genetics
Genes
Genomes
Genotype & phenotype
Green Fluorescent Proteins - genetics
GTP-Binding Proteins - genetics
GTP-Binding Proteins - metabolism
Humans
HUMDISEASE
Insects
Kinases
Male
Mice
Microscopy, Electron, Transmission - methods
Mitochondria - metabolism
Mitochondrial Diseases - genetics
Mitochondrial Diseases - metabolism
MOLNEURO
Mutation
Mutation - genetics
Nerve Degeneration - pathology
Phenotype
Phosphorylation
Photoreceptors
Proteins
Proteomics - methods
Purkinje Cells - metabolism
Purkinje Cells - ultrastructure
Retina - pathology
Retina - ultrastructure
Retinal Degeneration - genetics
Retinal Degeneration - physiopathology
Rodents
Serine-Type D-Ala-D-Ala Carboxypeptidase - genetics
Serine-Type D-Ala-D-Ala Carboxypeptidase - metabolism
Studies
Transduction, Genetic - methods
Transfection - methods
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Description
Summary: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. ► How loss of function of Nna1 causes pcd neurodegeneration in mice is unknown ► Loss of function of Drosophila Nna1 (NnaD) yielded pcd-like phenotypes ► Proteomics analysis of pcd retina linked Nna1 to metabolic pathways and mitochondria ► Nna proteins are in mitochondria, and their loss yields mitochondrial dysfunction
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2010.05.024