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Mitochondrial dysfunction in NnaD mutant flies and Purkinje cell degeneration mice reveals a role for Nna proteins in neuronal bioenergetics
- Source :
- Neuron. 66(6)
- Publication Year :
- 2010
-
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 three 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 orthologue (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, and suggest that pcd shares pathogenic features with neurodegenerative disorders such as Parkinson's disease.
- Subjects :
- Retinal degeneration
Male
Proteomics
Cerebellum
Mitochondrial Diseases
Purkinje cell
HUMDISEASE
Mitochondrion
Animals, Genetically Modified
Mice
Purkinje Cells
0302 clinical medicine
Transduction, Genetic
Drosophila Proteins
Cell Line, Transformed
0303 health sciences
General Neuroscience
Neurodegeneration
Retinal Degeneration
Serine-Type D-Ala-D-Ala Carboxypeptidase
3. Good health
Cell biology
Mitochondria
medicine.anatomical_structure
Phenotype
Drosophila
animal structures
Neuroscience(all)
Green Fluorescent Proteins
Oxidative phosphorylation
Biology
Transfection
MOLNEURO
Retina
Article
03 medical and health sciences
Microscopy, Electron, Transmission
GTP-Binding Proteins
medicine
otorhinolaryngologic diseases
Animals
Humans
Loss function
030304 developmental biology
medicine.disease
Molecular biology
Disease Models, Animal
Gene Expression Regulation
Mutation
Nerve Degeneration
CELLBIO
Energy Metabolism
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 10974199
- Volume :
- 66
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Neuron
- Accession number :
- edsair.doi.dedup.....915204b3cf5073eebc3bfc66d2bd93d0