Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease

DJ-1 mutations cause autosomal recessive early-onset Parkinson disease (PD). We report a model of PD pathology: the DJ1-C57 mouse. A subset of DJ-1–nullizygous mice, when fully backcrossed to a C57BL/6J background, display dramatic early-onset unilateral loss of dopaminergic (DA) neurons in their su...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-09, Vol.109 (39), p.15918-15923
Main Authors: Rousseaux, Maxime W. C, Marcogliese, Paul C, Qu, Dianbo, Hewitt, Sarah J, Seang, Sarah, Kim, Raymond H, Slack, Ruth S, Schlossmacher, Michael G, Lagace, Diane C, Mak, Tak W, Park, David S
Format: Article
Language:English
Subjects:
Animal models
Animals
Beadwork
Biological Sciences
Brain
brain stem
Cells
Disease models
Disease Models, Animal
Dopamine
Dopaminergic Neurons - metabolism
Dopaminergic Neurons - pathology
genes
Genetic mutation
Humans
Intracellular Signaling Peptides and Proteins
Locus Coeruleus - metabolism
Locus Coeruleus - pathology
Mice
Mice, Knockout
Mutation
Nerve Tissue Proteins
Neurons
Oncogene Proteins
Parkinson disease
Parkinson Disease - genetics
Parkinson Disease - metabolism
Parkinson Disease - pathology
Parkinson's disease
penetrance
phenotype
Phenotypes
Quantification
Rodents
sequence analysis
Sprouting
Substantia Nigra - metabolism
Substantia Nigra - pathology
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Description
Summary:DJ-1 mutations cause autosomal recessive early-onset Parkinson disease (PD). We report a model of PD pathology: the DJ1-C57 mouse. A subset of DJ-1–nullizygous mice, when fully backcrossed to a C57BL/6J background, display dramatic early-onset unilateral loss of dopaminergic (DA) neurons in their substantia nigra pars compacta , progressing to bilateral degeneration of the nigrostriatal axis with aging. In addition, these mice exhibit age-dependent bilateral degeneration at the locus ceruleus nucleus and display mild motor behavior deficits at aged time points. These findings effectively recapitulate the early stages of PD. Therefore, the DJ1-C57 mouse provides a tool to study the preclinical aspects of neurodegeneration. Importantly, by exome sequencing, we identify candidate modifying genes that segregate with the phenotype, providing potentially critical clues into how certain genes may influence the penetrance of DJ-1–related degeneration in mice.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1205102109