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. 2012 Sep 25;109(39):15918-23.
doi: 10.1073/pnas.1205102109. Epub 2012 Sep 10.

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

Maxime W C Rousseaux  1 , Paul C Marcogliese, Dianbo Qu, Sarah J Hewitt, Sarah Seang, Raymond H Kim, Ruth S Slack, Michael G Schlossmacher, Diane C Lagace, Tak W Mak, David S Park
Affiliations

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

Maxime W C Rousseaux et al. Proc Natl Acad Sci U S A. .

Erratum in

  • Proc Natl Acad Sci U S A. 2013 Jul 2;110(27):11212

Abstract

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/6 [corrected] 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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Young affected DJ1-C57 mice exhibit selective unilateral degeneration in their SNc. (A) Representative midbrain sections of DJ1-C57 affected (Top), DJ1-C57 Unaffected (Middle), and WT (Bottom) mice depicting TH staining in the SNc and VTA. (B and C) Quantification of A by stereology of total number of TH-positive cells in the SNc (B) and of CV-stained cells at the level of the MTN in the SNc (C). (D) Quantification of TH-positive neurons in the VTA of WT and DJ-1 affected mice. Note that WT, DJ1-C57 affected and DJ1-C57 unaffected are represented by blue, red, and yellow bars, respectively. Side A is depicted as solid shading and side B as hatched shading. NS, not significant (P > 0.05); ***P < 0.001; ANOVA, followed by Tukey’s LSD post hoc tests. Data are represented as means (n = 7–80 per group) ± SEM.
Fig. 2.
Fig. 2.
Widespread process disruption and aberrant striatal innervation in young affected DJ1-C57 mice. (A) Fiber sprouting in WT (Upper Left) and DJ1-C57 affected animals (Upper Right). Distribution of quantified uninterrupted process (TH+) length in a single vision plain (in microns) is presented (Lower). (B) Representative sections of striatum stained for ∆FosB in young WT (Left) and DJ1-C57 affected (Center) mice. (Right) Quantification of ∆FosB-positive puncta in the striatum. (C) Representative sections of the striatum stained for TH as in B. Quantification of striatal TH density is shown (Right). WT, DJ1-C57 affected, and DJ1-C57 unaffected are represented by blue, red, and yellow bars, respectively. Side A is depicted as solid shading and side B as hatched shading. NS, not significant (P > 0.05); *P < 0.05; **P < 0.01; ANOVA, followed by Tukey’s LSD post hoc tests. Data are represented as means (n = 3–11 per group) ± SEM.
Fig. 3.
Fig. 3.
Focal microgliosis in young affected DJ1-C57 mice. (A) Representative midbrain sections stained for CV in young WT and DJ1-C57 affected mice (1000× magnification). Thin arrows denote typical morphology of DA neurons of the SNc; thick arrows denote shrunken, dead nuclei; and arrowheads denote appearance of cells with altered morphology. (B) CD11b staining in the midbrain of young WT (Left) and DJ1-C57 affected (Right) mice was quantified and represented as the number of Cd11b-positive cells in the MTN region of the SNc. WT and DJ1-C57 affected are represented by blue and red bars, respectively. Side A is depicted as solid shading and side B as hatched shading. NS, not significant (P > 0.05); *P < 0.05; ANOVA, followed by Tukey’s LSD post hoc tests. Data are represented as means (n = 3–9 per group) ± SEM.
Fig. 4.
Fig. 4.
Aged DJ1-C57 mice exhibit bilateral DA and noradrenergic denervation in the brainstem. (A) Penetrance of unilateral phenotype over time. Penetrant threshold: greater than 40% loss of DA neurons on one side (side A) vs. the other (side B). (B) Total stereological counts of DA neurons in the SNc of WT and DJ1-C57 aged (15-mo) animals. (C) Representative striatal sections of aged (12–15 mo) WT (Upper Left) and DJ1-C57 (Lower Left) mice stained for TH. Quantification of TH expression in the striatum relative to the corpus callosum was performed in young and aged animals (Right). (D) Representative micrographs of LC sections in the pons stained for TH for either aged WT (Left) or aged DJ1-C57 (Center). Quantification of TH-positive neurons for both young and aged animals is shown (Right). (E) The grip test evaluated the capacity of the mouse to stay on an inverted metal grid for 60 s. (F) The pole test evaluated the latency of mice to descend a gauze-wrapped pole (in seconds). NS, not significant (P > 0.05); *P < 0.05; ANOVA, followed by Tukey’s LSD post hoc tests. Data are represented as means (n = 3–13 per group) ± SEM.
Fig. 5.
Fig. 5.
List of exonic variants unique to affected DJ1-C57 mice. (A) Schematic workflow of exome sequencing to determine candidate mutations in affected DJ1-C57 mice (vs. unaffected littermate controls). (B) Table of variants present in all three examined affected animals and no unaffected littermates. See Experimental Procedures for selection criteria.
Fig. 6.
Fig. 6.
DJ1-C57 preclinical model of DA neurodegeneration. (A) Altered representative micrographs reproduced with permission from the Mouse Brain Library [www.mbl.org; Rosen et al. (36)] depicting healthy (red) SNc, striatum, and LC in 6-wk-old DJ1-C57 mice or all WT groups examined. (B) Affected DJ1-C57 mice demonstrate unilateral DA cell loss in the SNc but not in the LC. (C) Aged DJ1-C57 mice exhibit widespread degeneration in their nigrostriatal tract, as well as their LC.
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