Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Aug 23:6:31701.
doi: 10.1038/srep31701.

Identification of Multiple QTLs Linked to Neuropathology in the Engrailed-1 Heterozygous Mouse Model of Parkinson's Disease

Zuzanna Kurowska  1   2   3 , Michael Jewett  1 , Per Ludvik Brattås  1 , Itzia Jimenez-Ferrer  1 , Xuyian Kenéz  1 , Tomas Björklund  4 , Ulrika Nordström  5 , Patrik Brundin  6 , Maria Swanberg  1
Affiliations

Identification of Multiple QTLs Linked to Neuropathology in the Engrailed-1 Heterozygous Mouse Model of Parkinson's Disease

Zuzanna Kurowska et al. Sci Rep. .

Abstract

Motor symptoms in Parkinson's disease are attributed to degeneration of midbrain dopaminergic neurons (DNs). Heterozygosity for Engrailed-1 (En1), one of the key factors for programming and maintenance of DNs, results in a parkinsonian phenotype featuring progressive degeneration of DNs in substantia nigra pars compacta (SNpc), decreased striatal dopamine levels and swellings of nigro-striatal axons in the SwissOF1-En1+/- mouse strain. In contrast, C57Bl/6-En1+/- mice do not display this neurodegenerative phenotype, suggesting that susceptibility to En1 heterozygosity is genetically regulated. Our goal was to identify quantitative trait loci (QTLs) that regulate the susceptibility to PD-like neurodegenerative changes in response to loss of one En1 allele. We intercrossed SwissOF1-En1+/- and C57Bl/6 mice to obtain F2 mice with mixed genomes and analyzed number of DNs in SNpc and striatal axonal swellings in 120 F2-En1+/- 17 week-old male mice. Linkage analyses revealed 8 QTLs linked to number of DNs (p = 2.4e-09, variance explained = 74%), 7 QTLs linked to load of axonal swellings (p = 1.7e-12, variance explained = 80%) and 8 QTLs linked to size of axonal swellings (p = 7.0e-11, variance explained = 74%). These loci should be of prime interest for studies of susceptibility to Parkinson's disease-like damage in rodent disease models and considered in clinical association studies in PD.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Neurodegeneration of TH-positive neurons in SNpc of the different mouse strains and intercrosses.
(a) Stereological quantification of DNs in SNpc at 17 weeks of age. Individual data points and the mean +/− S.D. are shown. The mean number of DNs in SwissOF1-wt was significantly higher than in all other groups; ****p < 0.0001, **p < 0.01, *p < 0.05. C57Bl/6-N4 mice have in average 97% C57Bl/6 background genome. Representative images used for stereological quantification with TH-positive staining in SNpc of SwissOF1 wt(b), SwissOF1-En1+/− (c), C57Bl/6 wt (d), C57Bl/6-N4-En1+/− (e), F2-En1+/+ (f), F2-En1+/− (g). Scale bar: 200 μm.
Figure 2
Figure 2. Genetic characteristics.
(a) Parental (P) SwissOF1-En1+/− females and C57Bl/6 males were intercrossed to obtain the F1 generation, from which En1+/− females and En1+/+ males were crossed to obtain F2-En1+/− and F2-En1+/+ male mice; (b) Genetic map of F2 population showing physical location of informative SNP markers; (c) Genotype frequency by F2 individual.
Figure 3
Figure 3. Results of the QTL analyses for the number of DNs in SNpc.
(a) Single QTL scan reveals no QTLs. Solid black - expectation-maximization; red - multiple imputation; blue - Haley-Knott; dotted line: p = 0.05. (b) Multiple QTL scan reveals 8 significant QTLs named En1a-h. (c) Refined chromosomal locations of En1a-h from multiple QTL scan; red lines between interacting loci. (d) Effect-plot for En1a. (e) Interaction plot for En1b:En1d.
Figure 4
Figure 4. Quantification and size of axonal swellings.
(a) Number of axonal swellings in parental SwissOF1-En1+/−, C57Bl/6-N4-En1+/−, F2-En1+/−. (b) Size of axonal swellings in parental SwissOF1-En1+/−, C57Bl/6-N4-En1+/−, F2-En1+/−. Axonal swellings indicated by arrows in dorso-lateral striatum of parental SwissOF1-En1+/− (c), C57Bl/6-N4-En1+/− (d) and F2-En1+/− (e). (f) Correlation of average size and number of axonal swelling (r = 0.62, p < 0.0001). (g) Correlation of average axonal swelling size vs number of DNs (n.s.). (h) Correlation of axonal swelling number vs number of DNs (n.s.). (i) Correlation of number of swellings per DN vs number of remaining DNs (r = −0.37, p < 0.001). **p < 0.01, *p < 0.05.
Figure 5
Figure 5. QTL analyses for the number of axonal swellings per number of remaing DNs.
(a) Single QTL analysis reveals one QTL at chromosome 15. Solid black - expectation-maximization; red - multiple imputation; blue - Haley-Knott; Dotted line - p = 0.05; (b) Multiple QTL analysis reveals 7 QTLs; (c) Refined positions of the 7 QTLs from multiple QTL scan. Lines between interacting loci; (d–f) Effect of En1i (d) En1j (e) and Enk (f) on axonal swellings per number of remaining DNs; (g) Interaction plot for En1i and En1k; (h) Interaction plot for En1i and En1j.
Figure 6
Figure 6. QTL analyses for the size of axonal swellings.
(a) Single QTL analysis shown no hits. Solid black - expectation-maximization; red - multiple imputation; blue - Haley-Knott; Dotted line - p = 0.05; (b) Multiple QTL analysis revealed 8 different loci; (c) Refined positions of the 8 QTLs from multiple QTL scan. Lines between interacting loci; (d,e) Effect of En1p (d) and En1s (e) on size of axonal swellings; (f–h) Interaction plots for En1p and En1q (f), En1p and En1r (g) and En1p and En1s (h).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Lim S. Y. & Lang A. E. The nonmotor symptoms of Parkinson’s disease–an overview. Movement disorders: official journal of the Movement Disorder Society 25 Suppl 1, S123–S130, doi: 10.1002/mds.22786 (2010). - DOI - PubMed
    1. Braak H., Ghebremedhin E., Rub U., Bratzke H. & Del Tredici K. Stages in the development of Parkinson’s disease-related pathology. Cell and tissue research 318, 121–134, doi: 10.1007/s00441-004-0956-9 (2004). - DOI - PubMed
    1. Hornykiewicz O. Dopamine (3-hydroxytyramine) and brain function. Pharmacological reviews 18, 925–964 (1966). - PubMed
    1. Riederer P. & Wuketich S. Time course of nigrostriatal degeneration in parkinson’s disease. A detailed study of influential factors in human brain amine analysis. J Neural Transm. 38, 277–301 (1976). - PubMed
    1. Houlden H. & Singleton A. B. The genetics and neuropathology of Parkinson’s disease. Acta Neuropathol. 124, 325–338, doi: 10.1007/s00401-012-1013-5 (2012). - DOI - PMC - PubMed

Publication types