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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 39; pp. 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: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.09.2012; National Acad Sciences
• 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
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1205102109

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.